Limits...
Interplay between Ubiquitin, SUMO, and Poly(ADP-Ribose) in the Cellular Response to Genotoxic Stress.

Pellegrino S, Altmeyer M - Front Genet (2016)

Bottom Line: Cells employ a complex network of molecular pathways to cope with endogenous and exogenous genotoxic stress.This multilayered response ensures that genomic lesions are efficiently detected and faithfully repaired in order to safeguard genome integrity.Both ubiquitylation and SUMOylation can lead to extensive chain-like protein modifications, a feature that is shared with yet another DNA damage-induced PTM, the modification of proteins with poly(ADP-ribose) (PAR).

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Mechanisms of Disease, University of Zurich Zürich, Switzerland.

ABSTRACT
Cells employ a complex network of molecular pathways to cope with endogenous and exogenous genotoxic stress. This multilayered response ensures that genomic lesions are efficiently detected and faithfully repaired in order to safeguard genome integrity. The molecular choreography at sites of DNA damage relies heavily on post-translational modifications (PTMs). Protein modifications with ubiquitin and the small ubiquitin-like modifier SUMO have recently emerged as important regulatory means to coordinate DNA damage signaling and repair. Both ubiquitylation and SUMOylation can lead to extensive chain-like protein modifications, a feature that is shared with yet another DNA damage-induced PTM, the modification of proteins with poly(ADP-ribose) (PAR). Chains of ubiquitin, SUMO, and PAR all contribute to the multi-protein assemblies found at sites of DNA damage and regulate their spatio-temporal dynamics. Here, we review recent advancements in our understanding of how ubiquitin, SUMO, and PAR coordinate the DNA damage response and highlight emerging examples of an intricate interplay between these chain-like modifications during the cellular response to genotoxic stress.

No MeSH data available.


Related in: MedlinePlus

Interplay between chain-like modifications at sites of DNA damage. (A) Interplay between ubiquitylation and SUMOylation through the STUbL RNF4, which ubiquitylates SUMOylated substrates to mediate their timely removal from repair sites. (B) Interplay between PARylation and ubiquitylation through the PTUbLs RNF146 and CHFR, which cooperate to dissociate automodified PARP1 from DNA break sites. (C) Productive interaction between PARylation and SUMOylation to stabilize the recruitment of the SLX4 complex. (D) Interplay between PARylation, SUMOylation, and ubiquitylation via the PAR-responsive SUMO ligase CBX4 and the SUMO-responsive ubiquitin ligase BMI1 to promote chromatin ubiquitylation in response to DNA damage. P, phosphorylation; Ub, ubiquitylation; S, SUMOylation; A, ADP-ribosylation.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4835507&req=5

Figure 2: Interplay between chain-like modifications at sites of DNA damage. (A) Interplay between ubiquitylation and SUMOylation through the STUbL RNF4, which ubiquitylates SUMOylated substrates to mediate their timely removal from repair sites. (B) Interplay between PARylation and ubiquitylation through the PTUbLs RNF146 and CHFR, which cooperate to dissociate automodified PARP1 from DNA break sites. (C) Productive interaction between PARylation and SUMOylation to stabilize the recruitment of the SLX4 complex. (D) Interplay between PARylation, SUMOylation, and ubiquitylation via the PAR-responsive SUMO ligase CBX4 and the SUMO-responsive ubiquitin ligase BMI1 to promote chromatin ubiquitylation in response to DNA damage. P, phosphorylation; Ub, ubiquitylation; S, SUMOylation; A, ADP-ribosylation.

Mentions: As noted above, the ubiquitylation and SUMOylation machineries are tightly interconnected and cooperate to reshape the chromatin landscape for proper repair (Bekker-Jensen and Mailand, 2011; Jackson and Durocher, 2013). An interesting direct link between the two systems is provided by SUMO-targeted ubiquitin ligases (STUbLs), readers of SUMO modifications that possess ubiquitin ligase activity and specifically modify SUMOylated substrates. The STUbL RNF4 is a prime example that recently emerged as important regulator of protein accumulation upon DNA breakage. RNF4 is recruited to DSBs via its SUMO interaction motifs and ubiquitylates SUMOylated DDR factors, thereby leading to their withdrawal from repair sites and initiating their proteasomal degradation (Galanty et al., 2012; Luo et al., 2012; Yin et al., 2012). Defective targeting by RNF4 enhances the retention of a subset of DDR factors and compromises the initiation of downstream events required for efficient repair. Among the proteins that are targeted by RNF4 is the adaptor protein MDC1, whose removal promotes access of the DNA end resection and HR machineries (Galanty et al., 2012; Luo et al., 2012; Yin et al., 2012). Once DNA end resection has occurred, RNF4 is again required for the extraction of the single-stranded DNA binding protein RPA, which in turn allows for the accumulation of BRCA2 and RAD51 on resected DNA (Galanty et al., 2012). Collectively, these findings suggest that SUMO-targeted ubiquitylation participates in the dismantling of the anti-resection barrier and promotes HR reactions. In support of this notion, the activity of RNF4 itself is regulated in a CDK-dependent manner, allowing it to fulfill its HR-promoting roles primarily in the S/G2 phases of the cell cycle (Figure 2A) (Luo et al., 2015; Kuo et al., 2016). Interestingly, the DNA damage-induced crosstalk between SUMOylation and ubiquitylation is not restricted to DSBs (Poulsen et al., 2013; Ragland et al., 2013; Gibbs-Seymour et al., 2015; van Cuijk et al., 2015), and SUMO-targeted ubiquitylation followed by targeted protein removal and/or degradation thus emerges as a common theme in the stepwise progression of DNA repair pathways.


Interplay between Ubiquitin, SUMO, and Poly(ADP-Ribose) in the Cellular Response to Genotoxic Stress.

Pellegrino S, Altmeyer M - Front Genet (2016)

Interplay between chain-like modifications at sites of DNA damage. (A) Interplay between ubiquitylation and SUMOylation through the STUbL RNF4, which ubiquitylates SUMOylated substrates to mediate their timely removal from repair sites. (B) Interplay between PARylation and ubiquitylation through the PTUbLs RNF146 and CHFR, which cooperate to dissociate automodified PARP1 from DNA break sites. (C) Productive interaction between PARylation and SUMOylation to stabilize the recruitment of the SLX4 complex. (D) Interplay between PARylation, SUMOylation, and ubiquitylation via the PAR-responsive SUMO ligase CBX4 and the SUMO-responsive ubiquitin ligase BMI1 to promote chromatin ubiquitylation in response to DNA damage. P, phosphorylation; Ub, ubiquitylation; S, SUMOylation; A, ADP-ribosylation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835507&req=5

Figure 2: Interplay between chain-like modifications at sites of DNA damage. (A) Interplay between ubiquitylation and SUMOylation through the STUbL RNF4, which ubiquitylates SUMOylated substrates to mediate their timely removal from repair sites. (B) Interplay between PARylation and ubiquitylation through the PTUbLs RNF146 and CHFR, which cooperate to dissociate automodified PARP1 from DNA break sites. (C) Productive interaction between PARylation and SUMOylation to stabilize the recruitment of the SLX4 complex. (D) Interplay between PARylation, SUMOylation, and ubiquitylation via the PAR-responsive SUMO ligase CBX4 and the SUMO-responsive ubiquitin ligase BMI1 to promote chromatin ubiquitylation in response to DNA damage. P, phosphorylation; Ub, ubiquitylation; S, SUMOylation; A, ADP-ribosylation.
Mentions: As noted above, the ubiquitylation and SUMOylation machineries are tightly interconnected and cooperate to reshape the chromatin landscape for proper repair (Bekker-Jensen and Mailand, 2011; Jackson and Durocher, 2013). An interesting direct link between the two systems is provided by SUMO-targeted ubiquitin ligases (STUbLs), readers of SUMO modifications that possess ubiquitin ligase activity and specifically modify SUMOylated substrates. The STUbL RNF4 is a prime example that recently emerged as important regulator of protein accumulation upon DNA breakage. RNF4 is recruited to DSBs via its SUMO interaction motifs and ubiquitylates SUMOylated DDR factors, thereby leading to their withdrawal from repair sites and initiating their proteasomal degradation (Galanty et al., 2012; Luo et al., 2012; Yin et al., 2012). Defective targeting by RNF4 enhances the retention of a subset of DDR factors and compromises the initiation of downstream events required for efficient repair. Among the proteins that are targeted by RNF4 is the adaptor protein MDC1, whose removal promotes access of the DNA end resection and HR machineries (Galanty et al., 2012; Luo et al., 2012; Yin et al., 2012). Once DNA end resection has occurred, RNF4 is again required for the extraction of the single-stranded DNA binding protein RPA, which in turn allows for the accumulation of BRCA2 and RAD51 on resected DNA (Galanty et al., 2012). Collectively, these findings suggest that SUMO-targeted ubiquitylation participates in the dismantling of the anti-resection barrier and promotes HR reactions. In support of this notion, the activity of RNF4 itself is regulated in a CDK-dependent manner, allowing it to fulfill its HR-promoting roles primarily in the S/G2 phases of the cell cycle (Figure 2A) (Luo et al., 2015; Kuo et al., 2016). Interestingly, the DNA damage-induced crosstalk between SUMOylation and ubiquitylation is not restricted to DSBs (Poulsen et al., 2013; Ragland et al., 2013; Gibbs-Seymour et al., 2015; van Cuijk et al., 2015), and SUMO-targeted ubiquitylation followed by targeted protein removal and/or degradation thus emerges as a common theme in the stepwise progression of DNA repair pathways.

Bottom Line: Cells employ a complex network of molecular pathways to cope with endogenous and exogenous genotoxic stress.This multilayered response ensures that genomic lesions are efficiently detected and faithfully repaired in order to safeguard genome integrity.Both ubiquitylation and SUMOylation can lead to extensive chain-like protein modifications, a feature that is shared with yet another DNA damage-induced PTM, the modification of proteins with poly(ADP-ribose) (PAR).

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Mechanisms of Disease, University of Zurich Zürich, Switzerland.

ABSTRACT
Cells employ a complex network of molecular pathways to cope with endogenous and exogenous genotoxic stress. This multilayered response ensures that genomic lesions are efficiently detected and faithfully repaired in order to safeguard genome integrity. The molecular choreography at sites of DNA damage relies heavily on post-translational modifications (PTMs). Protein modifications with ubiquitin and the small ubiquitin-like modifier SUMO have recently emerged as important regulatory means to coordinate DNA damage signaling and repair. Both ubiquitylation and SUMOylation can lead to extensive chain-like protein modifications, a feature that is shared with yet another DNA damage-induced PTM, the modification of proteins with poly(ADP-ribose) (PAR). Chains of ubiquitin, SUMO, and PAR all contribute to the multi-protein assemblies found at sites of DNA damage and regulate their spatio-temporal dynamics. Here, we review recent advancements in our understanding of how ubiquitin, SUMO, and PAR coordinate the DNA damage response and highlight emerging examples of an intricate interplay between these chain-like modifications during the cellular response to genotoxic stress.

No MeSH data available.


Related in: MedlinePlus