USP1 Is Required for Replication Fork Protection in BRCA1-Deficient Tumors

Lim, Kah Suan; Li, Heng; Roberts, Emma A.; Gaudiano, Emily F.; Clairmont, Connor S.; Sambel, Larissa A.; Ponnienselvan, Karthikeyan; Liu, Jessica C.; Yang, Chunyu; Kozono, David; Parmar, Kalindi; Yusufzai, Timur; Zheng, Ning; D’Andrea, Alan D.

doi:10.1016/j.molcel.2018.10.045

Cited by 103 publications

(90 citation statements)

References 80 publications

(147 reference statements)

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“…Recently, Lim et al 41 , reported that USP1 also possesses a DNA binding activity with specificity for forked DNA (i.e. Y-shaped DNA with a duplex arm) and provided evidence that DNA binding exerts a modest stimulation of the DUB activity of USP1-UAF1.…”

Section: Discussionmentioning

confidence: 99%

“…Y-shaped DNA with a duplex arm) and provided evidence that DNA binding exerts a modest stimulation of the DUB activity of USP1-UAF1. Furthermore, BRCA1-deficient cells expressing a truncated variant of USP1 deficient in DNA binding fail to deliver USP1-UAF1 to replication forks to act on the ubiquitinated form of the proliferating cell nuclear antigen (PCNA) and are, consequently, impaired for the ability to stabilize stressed DNA replication forks 41 . It will be of considerable interest to determine whether the DNA binding activity of UAF1 and RAD51AP1 is also needed for the preservation of stressed replication forks and if DNA binding by USP1 is germane for FANCD2 deubiquitination and HDR proficiency.…”

Section: Discussionmentioning

confidence: 99%

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DNA requirement in FANCD2 deubiquitination by USP1-UAF1-RAD51AP1 in the Fanconi anemia DNA damage response

et al. 2019

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Fanconi anemia (FA) is a multigenic disease of bone marrow failure and cancer susceptibility stemming from a failure to remove DNA crosslinks and other chromosomal lesions. Within the FA DNA damage response pathway, DNA-dependent monoubiquitinaton of FANCD2 licenses downstream events, while timely FANCD2 deubiquitination serves to extinguish the response. Here, we show with reconstituted biochemical systems, which we developed, that efficient FANCD2 deubiquitination by the USP1-UAF1 complex is dependent on DNA and DNA binding by UAF1. Surprisingly, we find that the DNA binding activity of the UAF1-associated protein RAD51AP1 can substitute for that of UAF1 in FANCD2 deubiquitination in our biochemical system. We also reveal the importance of DNA binding by UAF1 and RAD51AP1 in FANCD2 deubiquitination in the cellular setting. Our results provide insights into a key step in the FA pathway and help define the multifaceted role of the USP1-UAF1-RAD51AP1 complex in DNA damage tolerance and genome repair.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

DNA requirement in FANCD2 deubiquitination by USP1-UAF1-RAD51AP1 in the Fanconi anemia DNA damage response

et al. 2019

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“…Interestingly, while the depletion of Pol Kappa was epistatic to FANCD2 loss in regard to replication fork restart after HU, these two proteins were not epistatic to stalled fork resection after HU. In a separate study, USP1 loss was synthetically lethal to loss of BRCA1, and this phenotype was due to increased stalled replication fork resection, as lethality could be rescued by inhibition of MRE11 [35]. Furthermore, depletion of Pol Kappa, which is hyper-recruited to the stalled forks due to the elevated levels of PCNA-Ub from loss of USP1 [36], also led to a rescued phenotype of stalled fork protection, implying that in this case Pol Kappa promotes nucleolytic resection.…”

Section: Tls In the Protection Against Stalled Replication Fork Nuclementioning

confidence: 98%

Role of Y-family translesion DNA polymerases in replication stress: Implications for new cancer therapeutic targets

Tonzi

Huang

2019

DNA Repair

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DNA replication stress, defined as the slowing or stalling of replication forks, is considered an emerging hallmark of cancer and a major contributor to genomic instability associated with tumorigenesis [1]. Recent advances have been made in attempting to target DNA repair factors involved in alleviating replication stress to potentiate genotoxic treatments. Various inhibitors of ATR and Chk1, the two major kinases involved in the intra-S-phase checkpoint, are currently in Phase I and II clinical trials [2]. In addition, currently approved inhibitors of Poly-ADP Ribose Polymerase (PARP) show synthetic lethality in cells that lack double-strand break repair such as in BRCA½ deficient tumors [3]. These drugs have also been shown to exacerbate replication stress by creating a DNA-protein crosslink, termed PARP 'trapping', and this is now thought to contribute to the therapeutic efficacy. Translesion synthesis (TLS) is a mechanism whereby special repair DNA polymerases accommodate and tolerate various DNA lesions to allow for damage bypass and continuation of DNA replication [4]. This class of proteins is best characterized by the Y-family, encompassing DNA polymerases (Pols) Kappa, Eta, Iota, and Rev1. While best studied for their ability to bypass physical lesions in the DNA, there is accumulating evidence for these proteins in coping with various natural replication fork barriers and alleviating replication stress. In this mini-review, we will highlight some of these recent advances, and discuss why targeting the TLS pathway may be a mechanism of enhancing cancer associated replication stress. Exacerbation of replication stress can lead to increased genome instability, which can be toxic to cancer cells and represent a therapeutic vulnerability.

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“…USP1 had low prevalence in gene mutation, but was elevated in several human cancers 15 . In breast malignancy, USP1 was shown to promote triple negative breast cancer progression, but its function in ERα positive type is not clear 27 . Our study showed that USP1 stabilized ERα via inhibiting K48-linked poly-ubiquitination of ERα, which provided a novel insight of DUBs in modulating hormone signaling and breast cancer progression.…”

Section: Discussionmentioning

confidence: 99%

The deubiquitinating enzyme USP1 modulates ERα and modulates breast cancer progression

Niu¹,

Li²,

Feng³

et al. 2020

J. Cancer

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Breast cancer is one of the most common malignancies worldwide, while the luminal types (ERα positive) accounts for two third of all breast cancer cases. Although ERα positive breast cancer could be effective controlled by endocrine therapy, most of the patients will develop endocrine resistance, which becomes a headache clinical issue for breast cancer field. Endocrine resistance could be caused by multiple pathway disorders, the dys-regulation of ERα signaling might be a critical factor, which makes it urgent and important to reveal the potential molecular mechanism of ERα signaling. In our current study, we identified a new deubiquitination enzyme USP1 through screening the whole DUB (Deubiquitinases) siRNA library. The expression of USP1 is elevated in human breast cancer compared with normal mammary tissues. Importantly, USP1 expression levels are specially correlated with poor survival in ERα positive patients. USP1 depletion inhibited breast cancer cell progression and ERα signaling activity. Immuno-precipitation assays indicate that USP1 associates with ERα and promotes its stability possibly via inhibiting ERα K48-linked poly-ubiquitination. In conclusion, our data implicate a non-genomic mechanism by USP1 via stabilizing ERα protein controls ERα target gene expression linked to breast cancer progression.

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USP1 Is Required for Replication Fork Protection in BRCA1-Deficient Tumors

Cited by 103 publications

References 80 publications

DNA requirement in FANCD2 deubiquitination by USP1-UAF1-RAD51AP1 in the Fanconi anemia DNA damage response

DNA requirement in FANCD2 deubiquitination by USP1-UAF1-RAD51AP1 in the Fanconi anemia DNA damage response

Role of Y-family translesion DNA polymerases in replication stress: Implications for new cancer therapeutic targets

The deubiquitinating enzyme USP1 modulates ERα and modulates breast cancer progression

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