Last update 01 Nov 2024

REV1

Last update 01 Nov 2024

Basic Info

Synonyms

AIBP80, Alpha integrin-binding protein 80, DNA repair protein REV1

+ [4]

Introduction

Deoxycytidyl transferase involved in DNA repair. Transfers a dCMP residue from dCTP to the 3'-end of a DNA primer in a template-dependent reaction. May assist in the first step in the bypass of abasic lesions by the insertion of a nucleotide opposite the lesion. Required for normal induction of mutations by physical and chemical agents.

Drugs associated with REV1

JH-RE-06

Target

REV1

Mechanism

REV1 inhibitors

Active Org.-

Originator Org.

Duke University

Active Indication-

Inactive Indication

Neoplasms

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with REV1

100 Translational Medicine associated with REV1

0 Patents (Medical) associated with REV1

499

Literatures (Medical) associated with REV1

19 Sep 2024·Nature structural & molecular biology

Catalytic and noncatalytic functions of DNA polymerase κ in translesion DNA synthesis.

Article

Author: Zarantonello, Alessandra ; Duxin, Julien P ; Hendriks, Ivo A ; Nilsson, Jakob ; Hertz, Emil P T ; Benedict, Bente ; Slappendel, Laura ; Meeusen, Bob ; Nielsen, Michael L ; Davey, Norman E ; Semlow, Daniel ; Gallina, Irene ; Miller, Thomas C R ; Ambjørn, Sara M ; Sturla, Shana ; Carli, Alberto ; Sellés-Baiget, Selene ; Gadi, Sampath A

Translesion DNA synthesis (TLS) is a cellular process that enables the bypass of DNA lesions encountered during DNA replication and is emerging as a primary target of chemotherapy. Among vertebrate DNA polymerases, polymerase κ (Polκ) has the distinctive ability to bypass minor groove DNA adducts in vitro. However, Polκ is also required for cells to overcome major groove DNA adducts but the basis of this requirement is unclear. Here, we combine CRISPR base-editor screening technology in human cells with TLS analysis of defined DNA lesions in Xenopus egg extracts to unravel the functions and regulations of Polκ during lesion bypass. Strikingly, we show that Polκ has two main functions during TLS, which are differentially regulated by Rev1 binding. On the one hand, Polκ is essential to replicate across a minor groove DNA lesion in a process that depends on PCNA ubiquitylation but is independent of Rev1. On the other hand, through its cooperative interaction with Rev1 and ubiquitylated PCNA, Polκ appears to stabilize the Rev1-Polζ extension complex on DNA to allow extension past major groove DNA lesions and abasic sites, in a process that is independent of Polκ's catalytic activity. Together, our work identifies catalytic and noncatalytic functions of Polκ in TLS and reveals important regulatory mechanisms underlying the unique domain architecture present at the C-terminal end of Y-family TLS polymerases.

01 Sep 2024·Nature Structural & Molecular Biology

Cryo-EM structure of the Rev1–Polζ holocomplex reveals the mechanism of their cooperativity in translesion DNA synthesis

Article

Author: Malik, Radhika ; Ubarretxena-Belandia, Iban ; Prakash, Satya ; Prakash, Louise ; Aggarwal, Aneel K ; Johnson, Robert E

Rev1-Polζ-dependent translesion synthesis (TLS) of DNA is crucial for maintaining genome integrity. To elucidate the mechanism by which the two polymerases cooperate in TLS, we determined the cryogenic electron microscopic structure of the Saccharomyces cerevisiae Rev1-Polζ holocomplex in the act of DNA synthesis (3.53 Å). We discovered that a composite N-helix-BRCT module in Rev1 is the keystone of Rev1-Polζ cooperativity, interacting directly with the DNA template-primer and with the Rev3 catalytic subunit of Polζ. The module is positioned akin to the polymerase-associated domain in Y-family TLS polymerases and is set ideally to interact with PCNA. We delineate the full extent of interactions that the carboxy-terminal domain of Rev1 makes with Polζ and identify potential new druggable sites to suppress chemoresistance from first-line chemotherapeutics. Collectively, our results provide fundamental new insights into the mechanism of cooperativity between Rev1 and Polζ in TLS.

01 Sep 2024·DNA Repair

Methylation and hydroxymethylation of cytosine alter activity and fidelity of translesion DNA polymerases

Article

Author: Boldinova, Elizaveta O ; Zharkov, Dmitry O ; Novikova, Anna A ; Petrova, Daria V ; Shilkin, Evgeniy S ; Makarova, Alena V

Epigenetic cytosine methylation covers most of genomic CpG dinucleotides in human cells. In addition to common deamination-mediated mutagenesis at CpG sites, an alternative deamination-independent pathway associated with DNA polymerase activity was previously described. This mutagenesis is characterized by the TCG→TTG mutational signature and is believed to arise from dAMP misincorporation opposite 5-methylcytosine (mC) or its oxidized derivative 5-hydroxymethylcytosine (hmC) by B-family replicative DNA polymerases with disrupted proofreading 3→5'-exonuclease activity. In addition to being less stable and pro-mutagenic themselves, cytosine modifications also increase the risk of adjacent nucleotides damage, including the formation of 8-oxo-2'-deoxyguanosine (8-oxoG), a well-known mutagenic lesion. The effect of cytosine methylation on error-prone DNA polymerases lacking proofreading activity and involved in repair and DNA translesion synthesis remains unexplored. Here we analyze the efficiency and fidelity of translesion Y-family polymerases (Pol κ, Pol η, Pol ι and REV1) and primase-polymerase PrimPol opposite mC and hmC as well as opposite 8-oxoG adjacent to mC in the TCG context. We demonstrate that epigenetic cytosine modifications suppress Pol ι and REV1 activities and lead to increasing dAMP misincorporation by PrimPol, Pol κ and Pol ι in vitro. Cytosine methylation also increases misincorporation of dAMP opposite the adjacent 8-oxoG by PrimPol, decreases the TLS activity of Pol η opposite the lesion but increases dCMP incorporation opposite 8-oxoG by REV1. Altogether, these data suggest that methylation and hydroxymethylation of cytosine alter activity and fidelity of translesion DNA polymerases.

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REV1

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