DNA polymerase stalling, sister chromatid recombination and the BRCA genes

Scully, Ralph; Puget, Nadine; Vlasáková, Kateřina

doi:10.1038/sj.onc.1203971

Cited by 63 publications

(39 citation statements)

References 76 publications

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“…Large numbers of proteins, requiring varying degrees of modification (phosphorylation, ubiquitylation, etc. ), are needed for both normal DNA replication and for negotiating past damaged sites and restoring replication after premature arrest (Scully et al, 2000;Zou et al, 2002;Zou and Elledge, 2003). Consequently, the proteins that accumulate at replication forks are likely to be complex, dynamic, dose-and time-dependent aggregates that depend on the genetic constitution of the cell and the particular damage that caused the arrest.…”

Section: Discussionmentioning

confidence: 99%

Alternative recombination pathways in UV-irradiated XP variant cells

2005

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XP variant (XP-V) cells lack the damage-specific polymerase g and exhibit prolonged replication arrest after UV irradiation due to impaired bypass of UV photoproducts. To analyse the outcome of the arrested replication forks, homologous recombination (HR, Rad51 events) and fork breakage (Rad50 events) were assayed by immunofluorescent detection of foci-positive cells. Within 1 h of irradiation, XP-V cells showed more Rad51-positive cells than normal cells, while neither cell type showed an increase in Rad50 foci. Beyond 1 h, the frequency of Rad51-positive cells reached similar levels in both cell types, then declined at higher UV doses. At these later times, Rad50-positive cells increased with dose and to a greater extent in XP-V cells. Few cells were simultaneously positive for both sets of foci, suggesting a mutually exclusive recruitment of recombination proteins, or that these pathways operate at different stages during S phase. Analysis of cells containing a vector of tandemly arranged enhanced green fluorescent protein genes also showed that UV-induced HR was higher in XP-V cells. These results suggest that cells make an early commitment to HR, and that at later times a subset of arrested forks degrade into double-strand breaks, two alternative pathways that are greater in XP-V cells.

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Section: Discussionmentioning

confidence: 99%

Alternative recombination pathways in UV-irradiated XP variant cells

2005

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“…Certain wellcharacterized DNA adducting carcinogens, such as benzo-[a]-pyrene metabolites, interrupt replication fork progression and are also excised inefficiently from the genome. Carcinogens of this type may promote cancer by causing DNA polymerase stalling and, hence, by increasing demand on the HR/SCR pathway [27,28] or on alternative error-prone pathways such as translesional DNA synthesis (TLS).…”

Section: Relationship Between Dna Polymerase Stalling and Hrmentioning

confidence: 99%

“…Structurally, HU-induced lagging strand gaps may resemble DSGs, and the recruitment of BRCA1, BRCA2, Rad51 and their associated proteins to sites of replication arrest in HU-treated cells suggests a response to ssDNA, even in the absence of DSB formation. This led to the proposal that BRCA1 and BRCA2 function in daughter strand gap repair [11,28]. Efficient Rad51 focus formation at DSBs induced by laser scissors or ionizing radiation (IR) is dependent upon BRCA1 and BRCA2, and Rad51 retention on chromatin following HU treatment is impaired in the absence of wild-type BRCA2, suggesting a possible role for BRCA1 and 2 in loading Rad51 onto ssDNA [97][98][99][100].…”

Section: Role Of Brca1 and Brca2 In Hr Regulationmentioning

confidence: 99%

Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks

Nagaraju

Scully

2007

DNA Repair

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The hereditary breast and ovarian cancer predisposition genes, BRCA1 and BRCA2, participate in the repair of DNA double strand breaks by homologous recombination. Circumstantial evidence implicates these genes in recombinational responses to DNA polymerase stalling during the S phase of the cell cycle. These responses play a key role in preventing genomic instability and cancer. Here, we review the current literature implicating the BRCA pathway in HR at stalled replication forks and explore the hypothesis that BRCA1 and BRCA2 participate in the recombinational resolution of single stranded DNA lesions termed "daughter strand gaps", generated during replication across a damaged DNA template.

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“…Many types of damage impede the progression of replication forks, which results in the activation of a complex set of checkpoints involving multiple, parallel pathways. [13][14][15] With UV damage the actual replication fork movement either continues at normal rates, or stops completely at sites of damage. 16 At least three mechanisms are then brought into play ( Fig.…”

Section: Intra-s Checkpointsmentioning

confidence: 99%

DNA Replication in the Face of (In)surmountable Odds

Cleaver

Laposa²,

Limoli³

2003

Cell Cycle

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"It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material… Whether a specific enzyme is required to carry out the polymerization… remains to be seen." 1 ABSTRACTWe describe here a model for sequential recruitment of various enzymatic systems that maintain DNA replication fidelity in cells with damaged bases, especially those formed by ultraviolet (UV) irradiation. Systems of increasing complexity but decreasing fidelity are recruited to restore replication of damaged DNA. The first and most accurate response is nucleotide excision repair (NER) that is cell cycle-independent; next come various delaying cell cycle checkpoints that provide an extended time window for NER. These delay the onset of the S phase at the G 1 /S boundary, and inhibit the initiation of individual replicating units (replicons and clusters of replicons) within the S phase. When checkpoints fail to operate completely, DNA replication forks must negotiate damage and the loss of coding information on the parental DNA strands. Replication can be resumed using bypass polymerases, or alternative bypass mechanisms. Finally, if all else fails, replication forks may degrade to double strand breaks and recombinational processes then allow their reconstruction. A network of signaling kinases modulates the efficiency of many damage responsive proteins to tailor their activities and subcellular localizations by phosphorylation and dephosphorylation.

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DNA polymerase stalling, sister chromatid recombination and the BRCA genes

Cited by 63 publications

References 76 publications

Alternative recombination pathways in UV-irradiated XP variant cells

Alternative recombination pathways in UV-irradiated XP variant cells

Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks

DNA Replication in the Face of (In)surmountable Odds

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