Dysregulation of DNA polymerase κ recruitment to replication forks results in genomic instability

Ma, Jones; Colnaghi, Luca; Huang, Tony T.

doi:10.1038/emboj.2011.457

Cited by 62 publications

(89 citation statements)

References 68 publications

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“…USP1 depletion also increases spontaneous and UV-induced point mutation frequency by elevating PCNA-Ub (Huang et al 2006;Hendel et al 2011). Loss of USP1 results in aberrant engagement of Pol k to DNA, leading to a slowdown of replication fork progression and interference of DNA synthesis (Jones et al 2012). This may explain the intrinsic genome instability observed upon USP1 downregulation and further highlights the role of USP1 in maintaining genome stability by coordinating both FA and TLS pathways.…”

Section: Regulation Of Rev1 By the Fa Pathwaymentioning

confidence: 89%

Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway

Kim¹,

D’Andrea²

2012

Genes Dev.

443

499

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The maintenance of genome stability is critical for survival, and its failure is often associated with tumorigenesis. The Fanconi anemia (FA) pathway is essential for the repair of DNA interstrand cross-links (ICLs), and a germline defect in the pathway results in FA, a cancer predisposition syndrome driven by genome instability. Central to this pathway is the monoubiquitination of FANCD2, which coordinates multiple DNA repair activities required for the resolution of ICLs. Recent studies have demonstrated how the FA pathway coordinates three critical DNA repair processes, including nucleolytic incision, translesion DNA synthesis (TLS), and homologous recombination (HR). Here, we review recent advances in our understanding of the downstream ICL repair steps initiated by ubiquitin-mediated FA pathway activation.

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Section: Regulation Of Rev1 By the Fa Pathwaymentioning

confidence: 89%

Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway

Kim¹,

D’Andrea²

2012

Genes Dev.

443

499

View full text Add to dashboard Cite

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“…Thus, it is believed that USP1-mediated deubiquitination of FANCD2 is a required step for the FANCD2 activation and the functional FA pathway. USP1 and UAF1 are also implicated in regulating translesion synthesis (TLS), through regulating PCNA monoubiquitination and recruitment of TLS polymerase k. 14,28,29 PCNA was shown to be required for initiation of recombination-associated DNA synthesis. 30 Therefore PCNA also participates in the HR repair, although whether it requires USP1 and UAF1 for the process is not known.…”

Section: Discussionmentioning

confidence: 99%

The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair

et al. 2016

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USP1 deubiquitinating enzyme and its stoichiometric binding partner UAF1 play an essential role in promoting DNA homologous recombination (HR) repair in response to various types of DNA damaging agents. Deubiquitination of FANCD2 may be attributed to the key role of USP1-UAF1 complex in regulating HR repair, however whether USP1-UAF1 promotes HR repair independently of FANCD2 deubiquitination is not known. Here we show evidence that the USP1-UAF1 complex has a FANCD2-independent function in promoting HR repair. Proteomic search of UAF1-interacting proteins revealed that UAF1 associates with RAD51AP1, a RAD51-interacting protein implicated in HR repair. We show that UAF1 mediates the interaction between USP1 and RAD51AP1, and that depletion of USP1 or UAF1 led to a decreased stability of RAD51AP1. Protein interaction mapping analysis identified some key residues within RAD51AP1 required for interacting with the USP1-UAF1 complex. Cells expressing the UAF1 interactiondeficient mutant of RAD51AP1 show increased chromosomal aberrations in response to Mitomycin C treatment. Moreover, similar to the RAD51AP1 depleted cells, the cells expressing UAF1-interaction deficient RAD51AP1 display persistent RAD51 foci following DNA damage exposure, indicating that these factors regulate a later step during the HR repair. These data altogether suggest that the USP1-UAF1 complex promotes HR repair via multiple mechanisms: through FANCD2 deubiquitination, as well as by interacting with RAD51AP1.

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“…Surprisingly, the effect of USP1 modulation in DNA elongation after UV irradiation has not yet been reported. Instead, the role of USP1 in undamaged cells has been revealed in a pioneering study from the group of Tony T. Huang: USP1 prevents accumulation of micronuclei during unstressed replication by restraining excessive recruitment of Polκ to undamaged DNA synthesis [39]. Since USP1 expression is restricted to S, G2/M-phases by the E3 ligase APC/C(Cdh1) [40], high USP1 levels in S-phase might prevent Polκ loading at undamaged DNA replication forks.…”

Section: Negative Regulators Of Tlsmentioning

confidence: 99%

The identification of translesion DNA synthesis regulators: Inhibitors in the spotlight

2015

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Over the past half-century, we have become increasingly aware of the ubiquity of DNA damage. Under the constant exposure to exogenous and endogenous genomic stress, cells must attempt to replicate damaged DNA. The encounter of replication forks with DNA lesions triggers several cellular responses, including the activation of translesion DNA synthesis (TLS), which largely depends upon specialized DNA polymerases with flexible active sites capable of accommodating bulky DNA lesions. A detrimental aspect of TLS is its intrinsic mutagenic nature, and thus the activity of the TLS polymerases must ideally be restricted to synthesis on damaged DNA templates. Despite their potential clinical importance in chemotherapy, TLS inhibitors have been difficult to identify since a direct assay designed to quantify genomic TLS events is still unavailable. Herein we discuss the methods that have been used to validate TLS inhibitors such as USP1, p21 and Spartan, highlighting research that has revealed their contribution to the control of DNA synthesis on damaged and undamaged templates.

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Dysregulation of DNA polymerase κ recruitment to replication forks results in genomic instability

Cited by 62 publications

References 68 publications

Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway

Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway

The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair

The identification of translesion DNA synthesis regulators: Inhibitors in the spotlight

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