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Replication stress in Mammalian cells and its consequences for mitosis.

Gelot C, Magdalou I, Lopez BS - Genes (Basel) (2015)

Bottom Line: Replication stress, which primarily occurs during S phase, results in consequences during mitosis, jeopardizing chromosome segregation and, in turn, genomic stability.Alterations in mitosis occur in two types: 1) local alterations that correspond to breaks, rearrangements, intertwined DNA molecules or non-separated sister chromatids that are confined to the region of the replication dysfunction; 2) genome-wide chromosome segregation resulting from centrosome amplification (although centrosomes do not contain DNA), which amplifies the local replication stress to the entire genome.Here, we discuss the endogenous causes of replication perturbations, the mechanisms of replication fork restart and the consequences for mitosis, chromosome segregation and genomic stability.

View Article: PubMed Central - PubMed

Affiliation: Institut de Cancérologie Gustave Roussy, CNRS UMR 8200 and Université Paris Sud, Equipe labélisée "LIGUE 2014", 114, Rue Edouard Vaillant, 94805 Villejuif, France. camille.gelot@gustaveroussy.fr.

ABSTRACT
The faithful transmission of genetic information to daughter cells is central to maintaining genomic stability and relies on the accurate and complete duplication of genetic material during each cell cycle. However, the genome is routinely exposed to endogenous and exogenous stresses that can impede the progression of replication. Such replication stress can be an early cause of cancer or initiate senescence. Replication stress, which primarily occurs during S phase, results in consequences during mitosis, jeopardizing chromosome segregation and, in turn, genomic stability. The traces of replication stress can be detected in the daughter cells during G1 phase. Alterations in mitosis occur in two types: 1) local alterations that correspond to breaks, rearrangements, intertwined DNA molecules or non-separated sister chromatids that are confined to the region of the replication dysfunction; 2) genome-wide chromosome segregation resulting from centrosome amplification (although centrosomes do not contain DNA), which amplifies the local replication stress to the entire genome. Here, we discuss the endogenous causes of replication perturbations, the mechanisms of replication fork restart and the consequences for mitosis, chromosome segregation and genomic stability.

No MeSH data available.


Related in: MedlinePlus

Fork restarts by HR following replication stress. (A) Model of repair of blocking lesions. (A.1) DNA adducts obstruct DNA synthesis by replicative DNA polymerases. Fork progression on a damaged template might involve a repriming event downstream of the damage, which leaves a ssDNA gap behind the moving fork. Rad51 then nucleates on the ssDNA gaps and promotes the recombination with the sister chromatid to seal the gap. Other mechanisms might be involved in the bypass of DNA lesions such as translesion synthesis (TLS). (A.2) Model of fork regression at a stalled fork: A slowing down of fork velocity or fork arrest leads to a transient uncoupling of the helicase and polymerases, thus exposing ssDNA at the stalled fork. The fork reversion forms a “chicken foot” structure (i.e., the fork and the nascent strand, which is complementary, being annealed together to form a four-way junction). Cleavage of this structure might involve MUS81 and leads to single-ended DSB formation. (B) Model of broken-fork repair. A replication fork can be converted into single-ended DSBs following the passage of the fork through a nick or following cleavage by an endonuclease. The single-ended break is then resected and Rad51 nucleates on the exposed ssDNA and promotes recombination with the sister chromatid. The 3' end of the invading strand primes DNA synthesis, and the replisome has been proposed to be rebuilt from the extended d-loop structure. (C) Model of fork restarts at a collapsed fork. Fork collapse might arise from a stalled fork where the replisome fails to be maintained in a functional state or when the replisome encounters physical obstacles such as tightly DNA bound proteins or RNA/DNA hybrids. Resection of nascent strands might help the fork to regress (i.e., the fork moving backward without the annealing of nascent strands) and thus allow the 3' end of the nascent strand to be extruded. Rad51 nucleates on the exposed ssDNA and promotes recombination with the parental DNA duplex. The replisome could again be rebuilt from the extended d-loop.
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genes-06-00267-f002: Fork restarts by HR following replication stress. (A) Model of repair of blocking lesions. (A.1) DNA adducts obstruct DNA synthesis by replicative DNA polymerases. Fork progression on a damaged template might involve a repriming event downstream of the damage, which leaves a ssDNA gap behind the moving fork. Rad51 then nucleates on the ssDNA gaps and promotes the recombination with the sister chromatid to seal the gap. Other mechanisms might be involved in the bypass of DNA lesions such as translesion synthesis (TLS). (A.2) Model of fork regression at a stalled fork: A slowing down of fork velocity or fork arrest leads to a transient uncoupling of the helicase and polymerases, thus exposing ssDNA at the stalled fork. The fork reversion forms a “chicken foot” structure (i.e., the fork and the nascent strand, which is complementary, being annealed together to form a four-way junction). Cleavage of this structure might involve MUS81 and leads to single-ended DSB formation. (B) Model of broken-fork repair. A replication fork can be converted into single-ended DSBs following the passage of the fork through a nick or following cleavage by an endonuclease. The single-ended break is then resected and Rad51 nucleates on the exposed ssDNA and promotes recombination with the sister chromatid. The 3' end of the invading strand primes DNA synthesis, and the replisome has been proposed to be rebuilt from the extended d-loop structure. (C) Model of fork restarts at a collapsed fork. Fork collapse might arise from a stalled fork where the replisome fails to be maintained in a functional state or when the replisome encounters physical obstacles such as tightly DNA bound proteins or RNA/DNA hybrids. Resection of nascent strands might help the fork to regress (i.e., the fork moving backward without the annealing of nascent strands) and thus allow the 3' end of the nascent strand to be extruded. Rad51 nucleates on the exposed ssDNA and promotes recombination with the parental DNA duplex. The replisome could again be rebuilt from the extended d-loop.

Mentions: HR is an evolutionary process that plays a central role in the equilibrium of genome stability and diversity. HR is involved in the repair of DNA double strand breaks (DSBs) (Figure 1) and in replication fork restart (Figure 2) (see [87] for review).


Replication stress in Mammalian cells and its consequences for mitosis.

Gelot C, Magdalou I, Lopez BS - Genes (Basel) (2015)

Fork restarts by HR following replication stress. (A) Model of repair of blocking lesions. (A.1) DNA adducts obstruct DNA synthesis by replicative DNA polymerases. Fork progression on a damaged template might involve a repriming event downstream of the damage, which leaves a ssDNA gap behind the moving fork. Rad51 then nucleates on the ssDNA gaps and promotes the recombination with the sister chromatid to seal the gap. Other mechanisms might be involved in the bypass of DNA lesions such as translesion synthesis (TLS). (A.2) Model of fork regression at a stalled fork: A slowing down of fork velocity or fork arrest leads to a transient uncoupling of the helicase and polymerases, thus exposing ssDNA at the stalled fork. The fork reversion forms a “chicken foot” structure (i.e., the fork and the nascent strand, which is complementary, being annealed together to form a four-way junction). Cleavage of this structure might involve MUS81 and leads to single-ended DSB formation. (B) Model of broken-fork repair. A replication fork can be converted into single-ended DSBs following the passage of the fork through a nick or following cleavage by an endonuclease. The single-ended break is then resected and Rad51 nucleates on the exposed ssDNA and promotes recombination with the sister chromatid. The 3' end of the invading strand primes DNA synthesis, and the replisome has been proposed to be rebuilt from the extended d-loop structure. (C) Model of fork restarts at a collapsed fork. Fork collapse might arise from a stalled fork where the replisome fails to be maintained in a functional state or when the replisome encounters physical obstacles such as tightly DNA bound proteins or RNA/DNA hybrids. Resection of nascent strands might help the fork to regress (i.e., the fork moving backward without the annealing of nascent strands) and thus allow the 3' end of the nascent strand to be extruded. Rad51 nucleates on the exposed ssDNA and promotes recombination with the parental DNA duplex. The replisome could again be rebuilt from the extended d-loop.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4488665&req=5

genes-06-00267-f002: Fork restarts by HR following replication stress. (A) Model of repair of blocking lesions. (A.1) DNA adducts obstruct DNA synthesis by replicative DNA polymerases. Fork progression on a damaged template might involve a repriming event downstream of the damage, which leaves a ssDNA gap behind the moving fork. Rad51 then nucleates on the ssDNA gaps and promotes the recombination with the sister chromatid to seal the gap. Other mechanisms might be involved in the bypass of DNA lesions such as translesion synthesis (TLS). (A.2) Model of fork regression at a stalled fork: A slowing down of fork velocity or fork arrest leads to a transient uncoupling of the helicase and polymerases, thus exposing ssDNA at the stalled fork. The fork reversion forms a “chicken foot” structure (i.e., the fork and the nascent strand, which is complementary, being annealed together to form a four-way junction). Cleavage of this structure might involve MUS81 and leads to single-ended DSB formation. (B) Model of broken-fork repair. A replication fork can be converted into single-ended DSBs following the passage of the fork through a nick or following cleavage by an endonuclease. The single-ended break is then resected and Rad51 nucleates on the exposed ssDNA and promotes recombination with the sister chromatid. The 3' end of the invading strand primes DNA synthesis, and the replisome has been proposed to be rebuilt from the extended d-loop structure. (C) Model of fork restarts at a collapsed fork. Fork collapse might arise from a stalled fork where the replisome fails to be maintained in a functional state or when the replisome encounters physical obstacles such as tightly DNA bound proteins or RNA/DNA hybrids. Resection of nascent strands might help the fork to regress (i.e., the fork moving backward without the annealing of nascent strands) and thus allow the 3' end of the nascent strand to be extruded. Rad51 nucleates on the exposed ssDNA and promotes recombination with the parental DNA duplex. The replisome could again be rebuilt from the extended d-loop.
Mentions: HR is an evolutionary process that plays a central role in the equilibrium of genome stability and diversity. HR is involved in the repair of DNA double strand breaks (DSBs) (Figure 1) and in replication fork restart (Figure 2) (see [87] for review).

Bottom Line: Replication stress, which primarily occurs during S phase, results in consequences during mitosis, jeopardizing chromosome segregation and, in turn, genomic stability.Alterations in mitosis occur in two types: 1) local alterations that correspond to breaks, rearrangements, intertwined DNA molecules or non-separated sister chromatids that are confined to the region of the replication dysfunction; 2) genome-wide chromosome segregation resulting from centrosome amplification (although centrosomes do not contain DNA), which amplifies the local replication stress to the entire genome.Here, we discuss the endogenous causes of replication perturbations, the mechanisms of replication fork restart and the consequences for mitosis, chromosome segregation and genomic stability.

View Article: PubMed Central - PubMed

Affiliation: Institut de Cancérologie Gustave Roussy, CNRS UMR 8200 and Université Paris Sud, Equipe labélisée "LIGUE 2014", 114, Rue Edouard Vaillant, 94805 Villejuif, France. camille.gelot@gustaveroussy.fr.

ABSTRACT
The faithful transmission of genetic information to daughter cells is central to maintaining genomic stability and relies on the accurate and complete duplication of genetic material during each cell cycle. However, the genome is routinely exposed to endogenous and exogenous stresses that can impede the progression of replication. Such replication stress can be an early cause of cancer or initiate senescence. Replication stress, which primarily occurs during S phase, results in consequences during mitosis, jeopardizing chromosome segregation and, in turn, genomic stability. The traces of replication stress can be detected in the daughter cells during G1 phase. Alterations in mitosis occur in two types: 1) local alterations that correspond to breaks, rearrangements, intertwined DNA molecules or non-separated sister chromatids that are confined to the region of the replication dysfunction; 2) genome-wide chromosome segregation resulting from centrosome amplification (although centrosomes do not contain DNA), which amplifies the local replication stress to the entire genome. Here, we discuss the endogenous causes of replication perturbations, the mechanisms of replication fork restart and the consequences for mitosis, chromosome segregation and genomic stability.

No MeSH data available.


Related in: MedlinePlus