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In-vitro helix opening of M. tuberculosis oriC by DnaA occurs at precise location and is inhibited by IciA like protein.

Kumar S, Farhana A, Hasnain SE - PLoS ONE (2009)

Bottom Line: While the region between dnaA and dnaN gene is capable of autonomous replication, little is known about the interaction between DnaA initiator protein, oriC origin of replication sequences and their negative effectors of replication.M.tb rRv1985c, a homologue of E.coli IciA (Inhibitor of chromosomal initiation) protein, could inhibit DnaA-mediated in-vitro helix opening by specifically binding to A+T rich region of oriC, provided the open complex formation had not initiated. rIciA could also inhibit in-vitro replication of plasmid carrying the M.tb origin of replication.These results have a bearing on the functional role of the important regulator of M.tb chromosomal replication belonging to the LysR family of bacterial regulatory proteins in the context of latency.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular and Cellular Biology, CDFD, Hyderabad, India.

ABSTRACT

Background: Mycobacterium tuberculosis (M.tb), the pathogen that causes tuberculosis, is capable of staying asymptomatically in a latent form, persisting for years in very low replicating state, before getting reactivated to cause active infection. It is therefore important to study M.tb chromosome replication, specifically its initiation and regulation. While the region between dnaA and dnaN gene is capable of autonomous replication, little is known about the interaction between DnaA initiator protein, oriC origin of replication sequences and their negative effectors of replication.

Methodology/principal findings: By KMnO(4) mapping assays the sequences involved in open complex formation within oriC, mediated by M.tb DnaA protein, were mapped to position -500 to -518 with respect to the dnaN gene. Contrary to E. coli, the M.tb DnaA in the presence of non-hydrolysable analogue of ATP (ATPgammaS) was unable to participate in helix opening thereby pointing to the importance of ATP hydrolysis. Interestingly, ATPase activity in the presence of supercoiled template was higher than that observed for DnaA box alone. M.tb rRv1985c, a homologue of E.coli IciA (Inhibitor of chromosomal initiation) protein, could inhibit DnaA-mediated in-vitro helix opening by specifically binding to A+T rich region of oriC, provided the open complex formation had not initiated. rIciA could also inhibit in-vitro replication of plasmid carrying the M.tb origin of replication.

Conclusions/significance: These results have a bearing on the functional role of the important regulator of M.tb chromosomal replication belonging to the LysR family of bacterial regulatory proteins in the context of latency.

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Related in: MedlinePlus

M.tb helix opening by rDnaA occurs near position −500 to −518 within the A+T rich region and this is inhibited by rIciA.pUC_OriMtb was used as a template for helix opening in the presence of increasing amounts of rDnaA with γ32P labeled SeqOriR1 and the primer extension products were fractionated on 6% sequencing gel. (A) SeqOriR1 primer reads pUC_OriMtb from bottom. Lanes 2, 3 and 4 show KMnO4 probing in the presence of 25 ng, 50 ng and 75 ng DnaA. These and other primer extension products of various sizes were designated as 200 nt (a), 199 nt (b) and so on and are summarized in Figure 3F. (B) The upstream primer SeqOriR3 reads pUC_OriMtb from the top and anneals at position −40 of pUC18 vector backbone. The different lanes are: lane 6, no DnaA protein; lanes 7–10: 0.075, 0.1, 0.2 and 0.3 μg of rDnaA. Extension products of 79(g), 77(h), 76(i), 66(j), 65(k) and 63(l) nucleotides could be seen. (C) Primer SeqOriR2 (downstream primer) also reads pUC_OriMtb from the 3′- end. After KMnO4 modification and PCR amplification with γ32P labeled SeqOriR2, the primer extension products were fractionated on a 15% sequencing gel. Lane 12, control DNA where no DnaA protein is added; lanes 13–16: 0.075, 0.1, 0.2 and 0.3 μg of rDnaA. Extension products of 116(c), 113(d), 99(e) and 98(f) nucleotides could be seen. Non-specific extension products (ns) were also seen in all lanes even in control DnaA free lane.10 bp ladder was used as DNA molecular size marker (lane 1, 5 and 11) and shown on the left. (D) The reaction was carried out using 0.2 μg of DnaA protein. Helix opening was monitored by primer extension using SeqOriR1 on a 6% sequencing gel. The different lanes are: lane 2, without rIciA; lane 3–4: increasing amounts (0.2 μg and 0.4 μg) of IciA protein. Arrows correspond to the extension products of 200 and 199 nucleotides. (E) Primer SeqOriR3 (lanes 5–11) and SeqOriR2 (lanes 13–19) were used to monitor helix inhibition mediated by rIciA. All the lanes from 5–9 and 13–17 have 0.2 μg of DnaA protein; Lanes 6–9 and 14–17 have increasing amounts (0.2, 0.3, 0.4 and 0.5 μg) of IciA protein; lanes 10 and 18 have 0.5 μg of IciA protein; lanes 11 and 19 have no DnaA or IciA protein; and lane 12 represents 10 bp marker. Arrows on the left correspond to extension products of 79, 77, 76, 66, 65 and 63 nucleotides with primer SeqOriR3 and 113, 99 and 98 nucleotides with primer SeqOriR2. (F) The nucleotide sequence of the entire oriC region of M.tb. Letters underlined represents various primers. Amplification products obtained by primer SeqOriR1 are marked by [ ] brackets. “]” bracket represents start of primer extension product and “[” bracket represent end of the primer extension product. It could be noted that primer extension stops at T residue which is modified by KMnO4. The small letters “a” and “b” represent 200 nt and 199 nt band. Similarly the amplification products obtained by primer SeqOriR2 (direction of primer extension product is shown by arrow) are marked by {} bracket and the modified T residues “{” mapped by this primer are indicated by c, d, e and f which represent 116, 113, 99 and 98 nucleotide bands. Likewise the amplification products obtained by primer SeqOriR3 are marked by () bracket. Here “(” bracket marks the start of extension and “)” bracket marks the end of extension product. The modified T residue is shown by g, h, i, j, k and l which represent 79, 77, 76, 66, 65 and 63 bp bands respectively. Also the start of dnaN gene is indicated by an arrow. (G) KMnO4 reactive pyrimidines within the A+T rich oriC of M.tb. About 19 bp stretch of pUC_OriMtb becomes sensitive to KMnO4 modification (the reactive pyrimidines are indicated by arrow).
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pone-0004139-g003: M.tb helix opening by rDnaA occurs near position −500 to −518 within the A+T rich region and this is inhibited by rIciA.pUC_OriMtb was used as a template for helix opening in the presence of increasing amounts of rDnaA with γ32P labeled SeqOriR1 and the primer extension products were fractionated on 6% sequencing gel. (A) SeqOriR1 primer reads pUC_OriMtb from bottom. Lanes 2, 3 and 4 show KMnO4 probing in the presence of 25 ng, 50 ng and 75 ng DnaA. These and other primer extension products of various sizes were designated as 200 nt (a), 199 nt (b) and so on and are summarized in Figure 3F. (B) The upstream primer SeqOriR3 reads pUC_OriMtb from the top and anneals at position −40 of pUC18 vector backbone. The different lanes are: lane 6, no DnaA protein; lanes 7–10: 0.075, 0.1, 0.2 and 0.3 μg of rDnaA. Extension products of 79(g), 77(h), 76(i), 66(j), 65(k) and 63(l) nucleotides could be seen. (C) Primer SeqOriR2 (downstream primer) also reads pUC_OriMtb from the 3′- end. After KMnO4 modification and PCR amplification with γ32P labeled SeqOriR2, the primer extension products were fractionated on a 15% sequencing gel. Lane 12, control DNA where no DnaA protein is added; lanes 13–16: 0.075, 0.1, 0.2 and 0.3 μg of rDnaA. Extension products of 116(c), 113(d), 99(e) and 98(f) nucleotides could be seen. Non-specific extension products (ns) were also seen in all lanes even in control DnaA free lane.10 bp ladder was used as DNA molecular size marker (lane 1, 5 and 11) and shown on the left. (D) The reaction was carried out using 0.2 μg of DnaA protein. Helix opening was monitored by primer extension using SeqOriR1 on a 6% sequencing gel. The different lanes are: lane 2, without rIciA; lane 3–4: increasing amounts (0.2 μg and 0.4 μg) of IciA protein. Arrows correspond to the extension products of 200 and 199 nucleotides. (E) Primer SeqOriR3 (lanes 5–11) and SeqOriR2 (lanes 13–19) were used to monitor helix inhibition mediated by rIciA. All the lanes from 5–9 and 13–17 have 0.2 μg of DnaA protein; Lanes 6–9 and 14–17 have increasing amounts (0.2, 0.3, 0.4 and 0.5 μg) of IciA protein; lanes 10 and 18 have 0.5 μg of IciA protein; lanes 11 and 19 have no DnaA or IciA protein; and lane 12 represents 10 bp marker. Arrows on the left correspond to extension products of 79, 77, 76, 66, 65 and 63 nucleotides with primer SeqOriR3 and 113, 99 and 98 nucleotides with primer SeqOriR2. (F) The nucleotide sequence of the entire oriC region of M.tb. Letters underlined represents various primers. Amplification products obtained by primer SeqOriR1 are marked by [ ] brackets. “]” bracket represents start of primer extension product and “[” bracket represent end of the primer extension product. It could be noted that primer extension stops at T residue which is modified by KMnO4. The small letters “a” and “b” represent 200 nt and 199 nt band. Similarly the amplification products obtained by primer SeqOriR2 (direction of primer extension product is shown by arrow) are marked by {} bracket and the modified T residues “{” mapped by this primer are indicated by c, d, e and f which represent 116, 113, 99 and 98 nucleotide bands. Likewise the amplification products obtained by primer SeqOriR3 are marked by () bracket. Here “(” bracket marks the start of extension and “)” bracket marks the end of extension product. The modified T residue is shown by g, h, i, j, k and l which represent 79, 77, 76, 66, 65 and 63 bp bands respectively. Also the start of dnaN gene is indicated by an arrow. (G) KMnO4 reactive pyrimidines within the A+T rich oriC of M.tb. About 19 bp stretch of pUC_OriMtb becomes sensitive to KMnO4 modification (the reactive pyrimidines are indicated by arrow).

Mentions: For our helix-opening assay increasing amounts of DnaA protein (0.025–0.3 μg) were incubated in presence of 5 mM ATP with supercoiled pUC_OriMtb, as described. Primer SeqOriR1 annealed between position −292 to −320 of template strand (Figure 3A), primer SeqOriR2 annealed between positions −402 to −420 of the template strand (Figure 3C) and primer SeqOriR3 annealed at position of −40 of pUC18 (Figure 3B). Primer extension reaction carried out using SeqOriR1 and SeqOriR2 would therefore enable read outs from bottom (downstream) while SeqOriR3 will give readouts from top (upstream). The extension products were then fractionated on a standard (6% or 15% as shown in the legend) urea sequencing gel (Figure 3A, B and C). Helix opening could clearly be detected in the presence of 0.075 μg (Figure 3A, lane 4) of rDnaA protein but barely when 0.025 μg or 0.050 μg (Figure 3A, lanes 2–3) of rDnaA was used and this was evident from the presence of extension products (lane 4) of 199 nucleotides(a) and 200 nucleotides(b) corresponding to position −500 and −501 from the start of the dnaN gene. To further pinpoint the extent of helix opening another primer SeqOriR2 was utilized and the extension products were fractionated on 15% urea gel. As can be seen (Figure 3C, lanes 12–16) extension products corresponding to 98, 99, 113 and 116 nucleotides designated as f, e, d and c respectively, could be observed which correspond to position −500, −501, −515, −518 from the start of dnaN gene. Primer SeqOriR3 annealed at position of −40 of pUC18 and generates extension products (Figure 3B, lanes 6–10) of 63(l), 65(k), 66(j), 76(i), 77(h) and 79(g) nucleotides which represent position −518, −515, −514, −504, −503 and −501 respectively, from start of dnaN gene. Irrespective of the primers used, the extension products appeared as a function of concentration of DnaA protein with 0.2 μg (200 nM) being the most efficient after which there was no further concentration effect. These mapping data, generated with different primers, are summarized in Figure 3F. To conclude, our results reveal that a 19 bp stretch of M.tb oriC becomes sensitive to KMnO4 (Figure 3G) thereby demonstrating, for the first time, that in M.tb the duplex opening occurs near position −500 to −518 (from start of dnaN gene) which lies within the A+T rich region.


In-vitro helix opening of M. tuberculosis oriC by DnaA occurs at precise location and is inhibited by IciA like protein.

Kumar S, Farhana A, Hasnain SE - PLoS ONE (2009)

M.tb helix opening by rDnaA occurs near position −500 to −518 within the A+T rich region and this is inhibited by rIciA.pUC_OriMtb was used as a template for helix opening in the presence of increasing amounts of rDnaA with γ32P labeled SeqOriR1 and the primer extension products were fractionated on 6% sequencing gel. (A) SeqOriR1 primer reads pUC_OriMtb from bottom. Lanes 2, 3 and 4 show KMnO4 probing in the presence of 25 ng, 50 ng and 75 ng DnaA. These and other primer extension products of various sizes were designated as 200 nt (a), 199 nt (b) and so on and are summarized in Figure 3F. (B) The upstream primer SeqOriR3 reads pUC_OriMtb from the top and anneals at position −40 of pUC18 vector backbone. The different lanes are: lane 6, no DnaA protein; lanes 7–10: 0.075, 0.1, 0.2 and 0.3 μg of rDnaA. Extension products of 79(g), 77(h), 76(i), 66(j), 65(k) and 63(l) nucleotides could be seen. (C) Primer SeqOriR2 (downstream primer) also reads pUC_OriMtb from the 3′- end. After KMnO4 modification and PCR amplification with γ32P labeled SeqOriR2, the primer extension products were fractionated on a 15% sequencing gel. Lane 12, control DNA where no DnaA protein is added; lanes 13–16: 0.075, 0.1, 0.2 and 0.3 μg of rDnaA. Extension products of 116(c), 113(d), 99(e) and 98(f) nucleotides could be seen. Non-specific extension products (ns) were also seen in all lanes even in control DnaA free lane.10 bp ladder was used as DNA molecular size marker (lane 1, 5 and 11) and shown on the left. (D) The reaction was carried out using 0.2 μg of DnaA protein. Helix opening was monitored by primer extension using SeqOriR1 on a 6% sequencing gel. The different lanes are: lane 2, without rIciA; lane 3–4: increasing amounts (0.2 μg and 0.4 μg) of IciA protein. Arrows correspond to the extension products of 200 and 199 nucleotides. (E) Primer SeqOriR3 (lanes 5–11) and SeqOriR2 (lanes 13–19) were used to monitor helix inhibition mediated by rIciA. All the lanes from 5–9 and 13–17 have 0.2 μg of DnaA protein; Lanes 6–9 and 14–17 have increasing amounts (0.2, 0.3, 0.4 and 0.5 μg) of IciA protein; lanes 10 and 18 have 0.5 μg of IciA protein; lanes 11 and 19 have no DnaA or IciA protein; and lane 12 represents 10 bp marker. Arrows on the left correspond to extension products of 79, 77, 76, 66, 65 and 63 nucleotides with primer SeqOriR3 and 113, 99 and 98 nucleotides with primer SeqOriR2. (F) The nucleotide sequence of the entire oriC region of M.tb. Letters underlined represents various primers. Amplification products obtained by primer SeqOriR1 are marked by [ ] brackets. “]” bracket represents start of primer extension product and “[” bracket represent end of the primer extension product. It could be noted that primer extension stops at T residue which is modified by KMnO4. The small letters “a” and “b” represent 200 nt and 199 nt band. Similarly the amplification products obtained by primer SeqOriR2 (direction of primer extension product is shown by arrow) are marked by {} bracket and the modified T residues “{” mapped by this primer are indicated by c, d, e and f which represent 116, 113, 99 and 98 nucleotide bands. Likewise the amplification products obtained by primer SeqOriR3 are marked by () bracket. Here “(” bracket marks the start of extension and “)” bracket marks the end of extension product. The modified T residue is shown by g, h, i, j, k and l which represent 79, 77, 76, 66, 65 and 63 bp bands respectively. Also the start of dnaN gene is indicated by an arrow. (G) KMnO4 reactive pyrimidines within the A+T rich oriC of M.tb. About 19 bp stretch of pUC_OriMtb becomes sensitive to KMnO4 modification (the reactive pyrimidines are indicated by arrow).
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pone-0004139-g003: M.tb helix opening by rDnaA occurs near position −500 to −518 within the A+T rich region and this is inhibited by rIciA.pUC_OriMtb was used as a template for helix opening in the presence of increasing amounts of rDnaA with γ32P labeled SeqOriR1 and the primer extension products were fractionated on 6% sequencing gel. (A) SeqOriR1 primer reads pUC_OriMtb from bottom. Lanes 2, 3 and 4 show KMnO4 probing in the presence of 25 ng, 50 ng and 75 ng DnaA. These and other primer extension products of various sizes were designated as 200 nt (a), 199 nt (b) and so on and are summarized in Figure 3F. (B) The upstream primer SeqOriR3 reads pUC_OriMtb from the top and anneals at position −40 of pUC18 vector backbone. The different lanes are: lane 6, no DnaA protein; lanes 7–10: 0.075, 0.1, 0.2 and 0.3 μg of rDnaA. Extension products of 79(g), 77(h), 76(i), 66(j), 65(k) and 63(l) nucleotides could be seen. (C) Primer SeqOriR2 (downstream primer) also reads pUC_OriMtb from the 3′- end. After KMnO4 modification and PCR amplification with γ32P labeled SeqOriR2, the primer extension products were fractionated on a 15% sequencing gel. Lane 12, control DNA where no DnaA protein is added; lanes 13–16: 0.075, 0.1, 0.2 and 0.3 μg of rDnaA. Extension products of 116(c), 113(d), 99(e) and 98(f) nucleotides could be seen. Non-specific extension products (ns) were also seen in all lanes even in control DnaA free lane.10 bp ladder was used as DNA molecular size marker (lane 1, 5 and 11) and shown on the left. (D) The reaction was carried out using 0.2 μg of DnaA protein. Helix opening was monitored by primer extension using SeqOriR1 on a 6% sequencing gel. The different lanes are: lane 2, without rIciA; lane 3–4: increasing amounts (0.2 μg and 0.4 μg) of IciA protein. Arrows correspond to the extension products of 200 and 199 nucleotides. (E) Primer SeqOriR3 (lanes 5–11) and SeqOriR2 (lanes 13–19) were used to monitor helix inhibition mediated by rIciA. All the lanes from 5–9 and 13–17 have 0.2 μg of DnaA protein; Lanes 6–9 and 14–17 have increasing amounts (0.2, 0.3, 0.4 and 0.5 μg) of IciA protein; lanes 10 and 18 have 0.5 μg of IciA protein; lanes 11 and 19 have no DnaA or IciA protein; and lane 12 represents 10 bp marker. Arrows on the left correspond to extension products of 79, 77, 76, 66, 65 and 63 nucleotides with primer SeqOriR3 and 113, 99 and 98 nucleotides with primer SeqOriR2. (F) The nucleotide sequence of the entire oriC region of M.tb. Letters underlined represents various primers. Amplification products obtained by primer SeqOriR1 are marked by [ ] brackets. “]” bracket represents start of primer extension product and “[” bracket represent end of the primer extension product. It could be noted that primer extension stops at T residue which is modified by KMnO4. The small letters “a” and “b” represent 200 nt and 199 nt band. Similarly the amplification products obtained by primer SeqOriR2 (direction of primer extension product is shown by arrow) are marked by {} bracket and the modified T residues “{” mapped by this primer are indicated by c, d, e and f which represent 116, 113, 99 and 98 nucleotide bands. Likewise the amplification products obtained by primer SeqOriR3 are marked by () bracket. Here “(” bracket marks the start of extension and “)” bracket marks the end of extension product. The modified T residue is shown by g, h, i, j, k and l which represent 79, 77, 76, 66, 65 and 63 bp bands respectively. Also the start of dnaN gene is indicated by an arrow. (G) KMnO4 reactive pyrimidines within the A+T rich oriC of M.tb. About 19 bp stretch of pUC_OriMtb becomes sensitive to KMnO4 modification (the reactive pyrimidines are indicated by arrow).
Mentions: For our helix-opening assay increasing amounts of DnaA protein (0.025–0.3 μg) were incubated in presence of 5 mM ATP with supercoiled pUC_OriMtb, as described. Primer SeqOriR1 annealed between position −292 to −320 of template strand (Figure 3A), primer SeqOriR2 annealed between positions −402 to −420 of the template strand (Figure 3C) and primer SeqOriR3 annealed at position of −40 of pUC18 (Figure 3B). Primer extension reaction carried out using SeqOriR1 and SeqOriR2 would therefore enable read outs from bottom (downstream) while SeqOriR3 will give readouts from top (upstream). The extension products were then fractionated on a standard (6% or 15% as shown in the legend) urea sequencing gel (Figure 3A, B and C). Helix opening could clearly be detected in the presence of 0.075 μg (Figure 3A, lane 4) of rDnaA protein but barely when 0.025 μg or 0.050 μg (Figure 3A, lanes 2–3) of rDnaA was used and this was evident from the presence of extension products (lane 4) of 199 nucleotides(a) and 200 nucleotides(b) corresponding to position −500 and −501 from the start of the dnaN gene. To further pinpoint the extent of helix opening another primer SeqOriR2 was utilized and the extension products were fractionated on 15% urea gel. As can be seen (Figure 3C, lanes 12–16) extension products corresponding to 98, 99, 113 and 116 nucleotides designated as f, e, d and c respectively, could be observed which correspond to position −500, −501, −515, −518 from the start of dnaN gene. Primer SeqOriR3 annealed at position of −40 of pUC18 and generates extension products (Figure 3B, lanes 6–10) of 63(l), 65(k), 66(j), 76(i), 77(h) and 79(g) nucleotides which represent position −518, −515, −514, −504, −503 and −501 respectively, from start of dnaN gene. Irrespective of the primers used, the extension products appeared as a function of concentration of DnaA protein with 0.2 μg (200 nM) being the most efficient after which there was no further concentration effect. These mapping data, generated with different primers, are summarized in Figure 3F. To conclude, our results reveal that a 19 bp stretch of M.tb oriC becomes sensitive to KMnO4 (Figure 3G) thereby demonstrating, for the first time, that in M.tb the duplex opening occurs near position −500 to −518 (from start of dnaN gene) which lies within the A+T rich region.

Bottom Line: While the region between dnaA and dnaN gene is capable of autonomous replication, little is known about the interaction between DnaA initiator protein, oriC origin of replication sequences and their negative effectors of replication.M.tb rRv1985c, a homologue of E.coli IciA (Inhibitor of chromosomal initiation) protein, could inhibit DnaA-mediated in-vitro helix opening by specifically binding to A+T rich region of oriC, provided the open complex formation had not initiated. rIciA could also inhibit in-vitro replication of plasmid carrying the M.tb origin of replication.These results have a bearing on the functional role of the important regulator of M.tb chromosomal replication belonging to the LysR family of bacterial regulatory proteins in the context of latency.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular and Cellular Biology, CDFD, Hyderabad, India.

ABSTRACT

Background: Mycobacterium tuberculosis (M.tb), the pathogen that causes tuberculosis, is capable of staying asymptomatically in a latent form, persisting for years in very low replicating state, before getting reactivated to cause active infection. It is therefore important to study M.tb chromosome replication, specifically its initiation and regulation. While the region between dnaA and dnaN gene is capable of autonomous replication, little is known about the interaction between DnaA initiator protein, oriC origin of replication sequences and their negative effectors of replication.

Methodology/principal findings: By KMnO(4) mapping assays the sequences involved in open complex formation within oriC, mediated by M.tb DnaA protein, were mapped to position -500 to -518 with respect to the dnaN gene. Contrary to E. coli, the M.tb DnaA in the presence of non-hydrolysable analogue of ATP (ATPgammaS) was unable to participate in helix opening thereby pointing to the importance of ATP hydrolysis. Interestingly, ATPase activity in the presence of supercoiled template was higher than that observed for DnaA box alone. M.tb rRv1985c, a homologue of E.coli IciA (Inhibitor of chromosomal initiation) protein, could inhibit DnaA-mediated in-vitro helix opening by specifically binding to A+T rich region of oriC, provided the open complex formation had not initiated. rIciA could also inhibit in-vitro replication of plasmid carrying the M.tb origin of replication.

Conclusions/significance: These results have a bearing on the functional role of the important regulator of M.tb chromosomal replication belonging to the LysR family of bacterial regulatory proteins in the context of latency.

Show MeSH
Related in: MedlinePlus