TopBP1 functions with 53BP1 in the G1 DNA damage checkpoint

Cescutti, Rachele; Negrini, Simona; Kohzaki, Masaoki; Halazonetis, Thanos D.

doi:10.1038/emboj.2010.238

Cited by 84 publications

(90 citation statements)

References 67 publications

(118 reference statements)

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“…TopBP1 itself is known to localize to DSBs through additional phospho-specific interactions with other repair proteins, such as MDC1, 53BP1, and BRIT1 (Cescutti et al 2010;Wang et al 2011;Zhang et al 2014). This phosphorylation site on E2F1 is not conserved in other members of the E2F family of transcription factors (Liu et al 2003).…”

Section: Discussionmentioning

confidence: 99%

RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1

et al. 2016

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The retinoblastoma (RB) tumor suppressor is recognized as a master regulator that controls entry into the S phase of the cell cycle. Its loss leads to uncontrolled cell proliferation and is a hallmark of cancer. RB works by binding to members of the E2F family of transcription factors and recruiting chromatin modifiers to the promoters of E2F target genes. Here we show that RB also localizes to DNA double-strand breaks (DSBs) dependent on E2F1 and ATM kinase activity and promotes DSB repair through homologous recombination (HR), and its loss results in genome instability. RB is necessary for the recruitment of the BRG1 ATPase to DSBs, which stimulates DNA end resection and HR. A knock-in mutation of the ATM phosphorylation site on E2F1 (S29A) prevents the interaction between E2F1 and TopBP1 and recruitment of RB, E2F1, and BRG1 to DSBs. This knock-in mutation also impairs DNA repair, increases genomic instability, and renders mice hypersensitive to IR. Importantly, depletion of RB in osteosarcoma and breast cancer cell lines results in sensitivity to DNA-damaging drugs, which is further exacerbated by poly-ADP ribose polymerase (PARP) inhibitors. We uncovered a novel, nontranscriptional function for RB in HR, which could contribute to genome instability associated with RB loss.

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Section: Discussionmentioning

confidence: 99%

RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1

et al. 2016

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“…Rad9 53BP1 is also recruited by Dbp11 TopBP1 , forming a complex that restrains Dna2-mediated nucleolytic processing (Granata et al 2010;Pfander and Diffley 2011;Villa et al 2018). This seems conserved in human cells, where TOPBP1 stabilizes 53BP1 to the sites of damage to inhibit DSB resection (Cescutti et al 2010;Zimmermann et al 2013;Chapman et al 2013;Ochs et al 2016;Liu et al 2017) and in S. pombe where the 53BP1 orthologue, Crb2, specifically inhibits the RecQ-helicase-dependent long-range resection pathway (Leland et al 2018). In both S. pombe and mammalian cells, another resection inhibitor, Rev7 seems to be at play although its mechanism of action is unknown (Boersma et al 2015;Xu et al 2015;Leland et al 2018).…”

Section: Resection Is Regulated At Multiple Levelsmentioning

confidence: 99%

Keep moving and stay in a good shape to find your homologous recombination partner

Bordelet

Dubrana

2018

Curr Genet

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Genomic DNA is constantly exposed to damage. Among the lesion in DNA, double-strand breaks (DSB), because they disrupt the two strands of the DNA double helix, are the more dangerous. DSB are repaired through two evolutionary conserved mechanisms: Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR). Whereas NHEJ simply reseals the double helix with no or minimal processing, HR necessitates the formation of a 3′ssDNA through the processing of DSB ends by the resection machinery and relies on the recognition and pairing of this 3′ssDNA tails with an intact homologous sequence. Despite years of active research on HR, the manner by which the two homologous sequences find each other in the crowded nucleus, and how this modulates HR efficiency, only recently emerges. Here, we review recent advances in our understanding of the factors limiting the search of a homologous sequence during HR.

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“…[1][2][3][4][5] One of the proteins involved in recognizing a particular type of DNA damage, DNA double-strand breaks (DSBs), is p53 Binding Protein 1 (53BP1), a protein that participates both in checkpoint activation by inducing cell cycle arrest and in DNA DSB repair by stimulating non-homologous end joining. [6][7][8][9][10][11][12][13][14][15] 53BP1 contains a tandem tudor domain, between amino acids 1485-1602, which is critical for recruitment to sites of DNA DSBs. [16][17] The tudor domain binds to methylated lysines in the histone core; it can recognize histone H3 dimethylated on lysine 79 (H3K79me2) or histone H4 dimethylated on lysine 20 (H4K20me2) and inhibition of methylation of either of these residues partially compromises 53BP1 recruitment to sites of DNA DSBs.…”

Section: Introductionmentioning

confidence: 99%

Ubiquitin-H2AX fusions render 53BP1 recruitment to DNA damage sites independent of RNF8 or RNF168

et al. 2015

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The mammalian E3 ubiquitin ligases RNF8 and RNF168 facilitate recruitment of the DNA damage response protein 53BP1 to sites of DNA double-strand breaks (DSBs). The mechanism involves recruitment of RNF8, followed by recruitment of RNF168, which ubiquitinates histones H2A/H2AX on K15. 53BP1 then binds to nucleosomes at sites of DNA DSBs by recognizing, in addition to methyl marks, histone H2A/H2AX ubiquitinated on K15. We report here that expressing H2AX fusion proteins with N-terminal bulky moieties can rescue 53BP1 recruitment to sites of DNA DSBs in cells lacking RNF8 or RNF168 or in cells treated with proteasome inhibitors, in which histone ubiquitination at sites of DNA DSBs is compromised. The rescue required S139 at the C-terminus of the H2AX fusion protein and was occasionally accompanied by partial rescue of ubiquitination at sites of DNA DSBs. We conclude that recruitment of 53BP1 to sites of DNA DSBs is possible in the absence of RNF8 or RNF168, but still dependent on chromatin ubiquitination.

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TopBP1 functions with 53BP1 in the G1 DNA damage checkpoint

Cited by 84 publications

References 67 publications

RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1

RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1

Keep moving and stay in a good shape to find your homologous recombination partner

Ubiquitin-H2AX fusions render 53BP1 recruitment to DNA damage sites independent of RNF8 or RNF168

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