Abstract SY21-02: Oncometabolites suppress homologous recombination DNA repair by inhibition of chromatin remodeling at the DNA double-strand break

Abstract Chromatin remodeling is essential for effective repair of a DNA double strand break. KAT5 (S. pombe Mst1, human TIP60) is a MYST family histone acetyltransferase conserved from yeast to humans that coordinates various DNA damage response activities at a DNA double strand break (DSB), including histone remodeling and activation of the DNA damage checkpoint. In S. pombe, mutations in mst1+ causes sensitivity to DNA damaging drugs. Here we show that Mst1 is recruited to DSBs. Mutation of mst1+ disrupts recruitment of repair proteins and delays resection. These defects are partially rescued by deletion of pku70, which has been previously shown to antagonize repair by homologous recombination. These phenotypes of mst1 are similar to pht1-4KR, a non-acetylatable form of histone variant H2A.Z, which has been proposed to affect resection. Our data suggest that Mst1 functions to direct repair of DSBs towards homologous recombination pathways by modulating resection at the double strand break.

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Schizosaccharomyces pombe KAT5 contributes to resection and repair of a DNA double strand break

10.1101/2020.06.03.132316 ◽

2020 ◽

Author(s):

Tingting Li ◽

Ruben C. Petreaca ◽

Susan L. Forsburg

Keyword(s):

Dna Damage ◽

Homologous Recombination ◽

Chromatin Remodeling ◽

Dna Damage Response ◽

Histone Acetyltransferase ◽

Strand Break ◽

Double Strand Break ◽

Dna Damage Checkpoint ◽

Dna Double Strand Break ◽

Damage Response

AbstractChromatin remodeling is essential for effective repair of a DNA double strand break. KAT5 (S. pombe Mst1, human TIP60) is a MYST family histone acetyltransferase conserved from yeast to humans that coordinates various DNA damage response activities at a DSB, including histone remodeling and activation of the DNA damage checkpoint. In S. pombe, mutations in mst1+ causes sensitivity to DNA damaging drugs. Here we show that Mst1 is recruited to DSBs. Mutation of mst1+ disrupts recruitment of repair proteins and delays resection. These defects are partially rescued by deletion of pku70, which has been previously shown to antagonize repair by homologous recombination. These phenotypes of mst1 are similar to pht1-4KR, a non-acetylatable form of histone variant H2A.Z, which has been proposed to affect resection. These data suggest that Mst1 functions to direct repair of DSBs towards homologous recombination pathways by modulating resection at the double strand break.

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Faculty Opinions recommendation of Histone H2A.Z controls a critical chromatin remodeling step required for DNA double-strand break repair.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717988297.793472681 ◽

2013 ◽

Author(s):

Yamini Dalal

Keyword(s):

Chromatin Remodeling ◽

Strand Break ◽

Double Strand Break ◽

Double Strand Break Repair ◽

Dna Double Strand Break ◽

Break Repair

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Faculty Opinions recommendation of DNA repair. PAXX, a paralog of XRCC4 and XLF, interacts with Ku to promote DNA double-strand break repair.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725308917.793503937 ◽

2015 ◽

Author(s):

Susan Lees-Miller

Keyword(s):

Dna Repair ◽

Strand Break ◽

Double Strand Break ◽

Double Strand Break Repair ◽

Dna Double Strand Break ◽

Break Repair

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Formation of Large Palindromic DNA by Homologous Recombination of Short Inverted Repeat Sequences in Saccharomyces cerevisiae

Genetics ◽

10.1093/genetics/161.3.1065 ◽

2002 ◽

Vol 161 (3) ◽

pp. 1065-1075

Author(s):

David K Butler ◽

David Gillespie ◽

Brandi Steele

Keyword(s):

Homologous Recombination ◽

Inverted Repeat ◽

Excision Repair ◽

Strand Break ◽

Double Strand Break ◽

Repeat Sequence ◽

Inverted Repeat Sequence ◽

Repeat Sequences ◽

Dna Double Strand Break ◽

Intermolecular Reaction

Abstract Large DNA palindromes form sporadically in many eukaryotic and prokaryotic genomes and are often associated with amplified genes. The presence of a short inverted repeat sequence near a DNA double-strand break has been implicated in the formation of large palindromes in a variety of organisms. Previously we have established that in Saccharomyces cerevisae a linear DNA palindrome is efficiently formed from a single-copy circular plasmid when a DNA double-strand break is introduced next to a short inverted repeat sequence. In this study we address whether the linear palindromes form by an intermolecular reaction (that is, a reaction between two identical fragments in a head-to-head arrangement) or by an unusual intramolecular reaction, as it apparently does in other examples of palindrome formation. Our evidence supports a model in which palindromes are primarily formed by an intermolecular reaction involving homologous recombination of short inverted repeat sequences. We have also extended our investigation into the requirement for DNA double-strand break repair genes in palindrome formation. We have found that a deletion of the RAD52 gene significantly reduces palindrome formation by intermolecular recombination and that deletions of two other genes in the RAD52-epistasis group (RAD51 and MRE11) have little or no effect on palindrome formation. In addition, palindrome formation is dramatically reduced by a deletion of the nucleotide excision repair gene RAD1.

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Ubiquitylation-Mediated Fine-Tuning of DNA Double-Strand Break Repair

Cancers ◽

10.3390/cancers12061617 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1617

Author(s):

Barbara N. Borsos ◽

Hajnalka Majoros ◽

Tibor Pankotai

Keyword(s):

Dna Repair ◽

Strand Break ◽

Double Strand Break ◽

Fine Tuning ◽

Double Strand Break Repair ◽

Proper Function ◽

Dna Damages ◽

Regulatory Pathways ◽

Dna Double Strand Break ◽

Break Repair

The proper function of DNA repair is indispensable for eukaryotic cells since accumulation of DNA damages leads to genome instability and is a major cause of oncogenesis. Ubiquitylation and deubiquitylation play a pivotal role in the precise regulation of DNA repair pathways by coordinating the recruitment and removal of repair proteins at the damaged site. Here, we summarize the most important post-translational modifications (PTMs) involved in DNA double-strand break repair. Although we highlight the most relevant PTMs, we focus principally on ubiquitylation-related processes since these are the most robust regulatory pathways among those of DNA repair.

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Promyelocytic leukemia nuclear bodies support a late step in DNA double-strand break repair by homologous recombination

Journal of Cellular Biochemistry ◽

10.1002/jcb.24050 ◽

2011 ◽

pp. n/a-n/a ◽

Cited By ~ 11

Author(s):

Percy Luk Yeung ◽

Natalia G. Denissova ◽

Cara Nasello ◽

Zhanna Hakhverdyan ◽

J. Don Chen ◽

...

Keyword(s):

Homologous Recombination ◽

Strand Break ◽

Double Strand Break ◽

Promyelocytic Leukemia ◽

Nuclear Bodies ◽

Double Strand Break Repair ◽

Dna Double Strand Break ◽

Late Step ◽

Promyelocytic Leukemia Nuclear Bodies ◽

Break Repair

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Molecular Characterization of the Role of the Schizosaccharomyces pombe nip1+/ctp1+ Gene in DNA Double-Strand Break Repair in Association with the Mre11-Rad50-Nbs1 Complex

Molecular and Cellular Biology ◽

10.1128/mcb.01828-07 ◽

2008 ◽

Vol 28 (11) ◽

pp. 3639-3651 ◽

Cited By ~ 38

Author(s):

Yufuko Akamatsu ◽

Yasuto Murayama ◽

Takatomi Yamada ◽

Tomofumi Nakazaki ◽

Yasuhiro Tsutsui ◽

...

Keyword(s):

Dna Repair ◽

Schizosaccharomyces Pombe ◽

Sequence Similarity ◽

Strand Break ◽

Double Strand Break ◽

Double Strand Break Repair ◽

Dna Double Strand Breaks ◽

Epistasis Analysis ◽

Dna Double Strand Break ◽

Break Repair

ABSTRACT The Schizosaccharomyces pombe nip1 +/ctp1 + gene was previously identified as an slr (synthetically lethal with rad2) mutant. Epistasis analysis indicated that Nip1/Ctp1 functions in Rhp51-dependent recombinational repair, together with the Rad32 (spMre11)-Rad50-Nbs1 complex, which plays important roles in the early steps of DNA double-strand break repair. Nip1/Ctp1 was phosphorylated in asynchronous, exponentially growing cells and further phosphorylated in response to bleomycin treatment. Overproduction of Nip1/Ctp1 suppressed the DNA repair defect of an nbs1-s10 mutant, which carries a mutation in the FHA phosphopeptide-binding domain of Nbs1, but not of an nbs1 null mutant. Meiotic DNA double-strand breaks accumulated in the nip1/ctp1 mutant. The DNA repair phenotypes and epistasis relationships of nip1/ctp1 are very similar to those of the Saccharomyces cerevisiae sae2/com1 mutant, suggesting that Nip1/Ctp1 is a functional homologue of Sae2/Com1, although the sequence similarity between the proteins is limited to the C-terminal region containing the RHR motif. We found that the RxxL and CxxC motifs are conserved in Schizosaccharomyces species and in vertebrate CtIP, originally identified as a cofactor of the transcriptional corepressor CtBP. However, these two motifs are not found in other fungi, including Saccharomyces and Aspergillus species. We propose that Nip1/Ctp1 is a functional counterpart of Sae2/Com1 and CtIP.

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