14-3-3 Proteins Restrain the Exo1 Nuclease to Prevent Overresection

Chen, Xiaoqing; Kim, In Kwon; Honaker, Yuchi; Paudyal, Sharad C.; Koh, Won Kyun; Sparks, Melanie; Li, Shan; Piwnica‐Worms, Helen; Ellenberger, Tom; You, Zhipeng

doi:10.1074/jbc.m115.644005

Cited by 28 publications

(33 citation statements)

References 72 publications

(87 reference statements)

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“…To dissect how resection is initiated at clean DSBs in the presence of all resection activities, we used the Xenopus nucleoplasmic extract (NPE) isolated from synthetic nuclei—a cell-free system that faithfully recapitulates the proper DNA damage response in S and G2 phases of the cell cycle (52,59,63,81–86). Our results indicate that like blocked DSBs, resection initiation of clean DSBs also occurs via endocleavage of the 5′ strand DNA; however, Dna2, but not CtIP–MRN, is the primary nuclease for this process.…”

Section: Introductionmentioning

confidence: 99%

Dna2 initiates resection at clean DNA double-strand breaks

Paudyal

Yan

et al. 2017

Nucleic Acids Research

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Nucleolytic resection of DNA double-strand breaks (DSBs) is essential for both checkpoint activation and homology-mediated repair; however, the precise mechanism of resection, especially the initiation step, remains incompletely understood. Resection of blocked ends with protein or chemical adducts is believed to be initiated by the MRN complex in conjunction with CtIP through internal cleavage of the 5′ strand DNA. However, it is not clear whether resection of clean DSBs with free ends is also initiated by the same mechanism. Using the Xenopus nuclear extract system, here we show that the Dna2 nuclease directly initiates the resection of clean DSBs by cleaving the 5′ strand DNA ∼10–20 nucleotides away from the ends. In the absence of Dna2, MRN together with CtIP mediate an alternative resection initiation pathway where the nuclease activity of MRN apparently directly cleaves the 5′ strand DNA at more distal sites. MRN also facilitates resection initiation by promoting the recruitment of Dna2 and CtIP to the DNA substrate. The ssDNA-binding protein RPA promotes both Dna2- and CtIP–MRN-dependent resection initiation, but a RPA mutant can distinguish between these pathways. Our results strongly suggest that resection of blocked and clean DSBs is initiated via distinct mechanisms.

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Section: Introductionmentioning

confidence: 99%

Dna2 initiates resection at clean DNA double-strand breaks

Paudyal

Yan

et al. 2017

Nucleic Acids Research

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“…Together, these observations suggest that checkpoint-mediated phosphorylation of Exo1 inhibits its activity to terminate the resection. Interestingly, Exo1 interacts with phospho-peptide binding proteins 14-3-3s, and this interaction inhibits its damage recruitment and subsequent DNA resection [127][128][129]. Thus, it is plausible that phosphorylation of Exo1 by ATM, ATR, or their downstream kinases promotes the interaction of Exo1 with 14-3-3s, preventing its association with DNA damage, thereby promoting resection termination (Fig.…”

Section: Termination Of Resectionmentioning

confidence: 99%

“…3). Disruption of the Exo1-14-3-3 interaction causes over-resection and increased sensitivity to DNA damage [127]. Exo1 activity in DSB resection may also be regulated by post-translational modifications such as phosphorylation, SUMOylation, and ubiquitination.…”

Section: Regulation Of Resection By 53bp1 and Brca1mentioning

confidence: 99%

“…Moreover, over-resection (e.g. by disrupting Exo1-14-3-3 interaction) increases cellular sensitivity to DNA damage, and thus may also be exploited for cancer treatment [127].…”

Section: Dna Resection At Telomeres Stalled Replication Forks and Hmentioning

confidence: 99%

“…Over-resection may result from unscheduled initiation, uncontrolled extension, or untimely termination. The function of Exo1 in resection is restrained by 14-3-3 proteins, which limit the damage recruitment of Exo1 by suppressing the binding of Exo1 to poly(ADP-ribose) (PAR) and PCNA, both of which promote Exo1's damage association [104,127,186] (Fig. 3).…”

Section: Regulation Of Resection By 53bp1 and Brca1mentioning

confidence: 99%

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Sharpening the ends for repair: mechanisms and regulation of DNA resection

Paudyal¹,

You²

2016

ABBS

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DNA end resection is a key process in the cellular response to DNA double-strand break damage that is essential for genome maintenance and cell survival. Resection involves selective processing of 5′ ends of broken DNA to generate ssDNA overhangs, which in turn control both DNA repair and checkpoint signaling. DNA resection is the first step in homologous recombination-mediated repair and a prerequisite for the activation of the ataxia telangiectasia mutated and Rad3-related (ATR)-dependent checkpoint that coordinates repair with cell cycle progression and other cellular processes. Resection occurs in a cell cycle-dependent manner and is regulated by multiple factors to ensure an optimal amount of ssDNA required for proper repair and genome stability. Here, we review the latest findings on the molecular mechanisms and regulation of the DNA end resection process and their implications for cancer formation and treatment.

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EXO1 (Exonuclease 1)

Rasmussen¹,

Keijzers²

2016

Encyclopedia of Signaling Molecules

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14-3-3 Proteins Restrain the Exo1 Nuclease to Prevent Overresection

Cited by 28 publications

References 72 publications

Dna2 initiates resection at clean DNA double-strand breaks

Dna2 initiates resection at clean DNA double-strand breaks

Sharpening the ends for repair: mechanisms and regulation of DNA resection

EXO1 (Exonuclease 1)

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