A conserved pathway to activate BRCA1-dependent ubiquitylation at DNA damage sites

Polanowska, Jolanta; Martin, Julie S.; García‐Muse, Tatiana; Petalcorin, Mark I.R.; Boulton, Simon J.

doi:10.1038/sj.emboj.7601102

Cited by 145 publications

(201 citation statements)

References 44 publications

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“…2b, c). Furthermore, ubiquitination events mediated by the breast cancer tumour suppressor protein BRCA1, triggered by single-strand DNA (ssDNA) accumulation in S-phase 15 , are also induced in 15% of HCLK2-depleted cells compared with 2% of cells with control siRNA (Fig. 2b, c …”

Section: Hclk2 Interacts With Components Of the S-phase Checkpointmentioning

confidence: 99%

HCLK2 is essential for the mammalian S-phase checkpoint and impacts on Chk1 stability

et al. 2007

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Here, we show that the human homologue of the Caenorhabditis elegans biological clock protein CLK-2 (HCLK2) associates with the S-phase checkpoint components ATR, ATRIP, claspin and Chk1. Consistent with a critical role in the S-phase checkpoint, HCLK2-depleted cells accumulate spontaneous DNA damage in S-phase, exhibit radio-resistant DNA synthesis, are impaired for damage-induced monoubiquitination of FANCD2 and fail to recruit FANCD2 and Rad51 (critical components of the Fanconi anaemia and homologous recombination pathways, respectively) to sites of replication stress. Although Thr 68 phosphorylation of the checkpoint effector kinase Chk2 remains intact in the absence of HCLK2, claspin phosphorylation and degradation of the checkpoint phosphatase Cdc25A are compromised following replication stress as a result of accelerated Chk1 degradation. ATR phosphorylation is known to both activate Chk1 and target it for proteolytic degradation, and depleting ATR or mutation of Chk1 at Ser 345 restored Chk1 protein levels in HCLK2-depleted cells. We conclude that HCLK2 promotes activation of the S-phase checkpoint and downstream repair responses by preventing unscheduled Chk1 degradation by the proteasome.The DNA damage response (DDR) is a complex process involving the orchestration of highly specialized cell-cycle checkpoints that need to be rapidly activated following the detection of damaged DNA. Each of these signalling cascades involves several unique and overlapping factors -classified as sensors, mediators, transducers and effectors -that ultimately lead to the spatio-temporal assembly of multi-protein complexes at the site of damage 1,2 . The functional importance of checkpoints in maintaining genome stability is highlighted by their conservation throughout eukaryotes. As such, defective checkpoint pathways in human cells leads to the accumulation of aberrant DNA and an increased risk of cancer progression, evident from the many human disease syndromes that result from defects in checkpoint factors 3,4 . Therefore, it is important to understand these complex mechanisms at the molecular level to further our knowledge of cancer progression and treatment.Checkpoints operate at the G1-S, S and G2-M boundaries of the cell cycle and are controlled by the ATM-Chk2 and ATR-Chk1 pathways. The S-phase checkpoint, which is under the control of the ATR-Chk1 pathway, has an essential role in maintaining replication-fork integrity during normal S-phase by preventing the collapse of stalled replication forks. The S-phase checkpoint also coordinates cell-cycle arrest and subsequent DNA-repair events when the replication fork encounters DNA damage 5,3,6 . Activation and recruitment of the Fanconi anaemia and homologous recombination-repair pathways to sites of replication stress requires an intact S-phase checkpoint 7 .Recent work in mouse models has highlighted a surprising, yet highly important link between biological clock proteins and the DDR 8,9 . It has been shown that two clock proteins, Per1 and Prd4, have integral roles...

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Section: Hclk2 Interacts With Components Of the S-phase Checkpointmentioning

confidence: 99%

HCLK2 is essential for the mammalian S-phase checkpoint and impacts on Chk1 stability

et al. 2007

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“…The BRCA1 RING domain interaction with the E2 enzyme Ubch5c is necessary for autoubiquitylation via K6-linked ubiquitin in vitro (Wu-Baer et al, 2003;Nishikawa et al, 2004). K6-Ub foci are present at DSBs in both a BRCA1-and Ubch5c-dependent manner (Morris and Solomon, 2004;Polanowska et al, 2006), which suggests that BRCA1 deposits factors are necessary to amplify signals for repair and checkpoint responses.…”

Section: Principles Of Dsb Recognitionmentioning

confidence: 99%

The ubiquitin landscape at DNA double-strand breaks

Messick¹,

Greenberg²

2009

J Exp Med

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“…Although the preferred linkage for polyubiquitylation in vitro appears to be an unconventional one involving lysine 6 of ubiquitin, BRCA1/BARD1 may also catalyze other linkages [111,112]. Not all of these ubiquitin linkages are associated with protein degradation, and detectable foci of ubiquitylation at DNA damage sites are dependent upon BRCA1 [113,114]. A number of cellular targets of the BRCA1/ BARD1 E3 ubiquitin ligase have been proposed, but the list of direct targets of BRCA1/ BARD1 is probably incomplete [115,116].…”

Section: Molecular Functions Of Brca1 and Brca2mentioning

confidence: 99%

“…An intact RING domain is necessary for efficient BRCA1-mediated DSB repair [91], and several cancer-predisposing point mutant alleles of BRCA1 affect the RING domain, inactivating its E3 ubiquitin ligase function [108,117]. E3 ubiquitin ligase activity in BRCA1 immunoprecipitates is enhanced following exposure of cells to IR, raising the possibility that this activity is regulated by DNA damage signaling [114].…”

Section: Molecular Functions Of Brca1 and Brca2mentioning

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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A conserved pathway to activate BRCA1-dependent ubiquitylation at DNA damage sites

Cited by 145 publications

References 44 publications

HCLK2 is essential for the mammalian S-phase checkpoint and impacts on Chk1 stability

HCLK2 is essential for the mammalian S-phase checkpoint and impacts on Chk1 stability

The ubiquitin landscape at DNA double-strand breaks

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

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