Human single-stranded DNA binding proteins: guardians of genome stability

Wu, Yuanzhong; Lu, Jinping; Kang, Tiebang

doi:10.1093/abbs/gmw044

Cited by 46 publications

(37 citation statements)

References 116 publications

(150 reference statements)

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“…To avoid degradation by cellular enzymes like A3s, and to promote DNA processing the ssDNA generated during DNA replication, recombination, and transcription is protected by ssDNA binding proteins Replication Protein A (RPA) or RAD51 [197,198]. A3 enzymes must be able to breach this protective barrier to access the ssDNA.…”

Section: Role Of Apobec In Somatic Mutagenesismentioning

confidence: 99%

Biochemical Basis of APOBEC3 Deoxycytidine Deaminase Activity on Diverse DNA Substrates

2018

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Apolipoprotein B mRNA-editing enzyme-catalytic, polypeptide-like 3 (APOBEC3) enzymes are a family of single-stranded (ss)DNA cytosine deaminases that serve as a host restriction factors for retrotransposons and viruses that contain a ssDNA intermediate. While the APOBEC3 family was originally expanded to restrict endogenous retroelements, the majority of these targets are now inactivated and the family has been found to act on different targets, such as viral ssDNA as a mechanism of viral defense. Some of the family members also catalyze "offtarget" deaminations in human ssDNA and have been implicated in somatic mutagenesis that can lead to cancer.My PhD thesis research investigated the biochemical mechanisms underlying both the benefits and the risks of the A3 family of enzymes. The central hypothesis of this work is that A3 enzymes have evolved distinct biochemical mechanisms to deaminate ssDNA that differentiate A3 restriction of retroelements and retroviruses from A3-induced somatic mutagenesis.Therefore, we investigated the biochemical mechanisms the A3 enzymes utilize during restriction of Human Immunodeficiency Virus (HIV) in both deamination-dependent and deaminationindependent modes, as well as the unique mechanisms employed during mutation of genomic DNA. There are seven APOBEC3 members (A-H, excluding E) and of these, four members (A3D, A3F, A3G, A3H) have been identified to restrict HIV replication in CD4 T+ cells, and currently three members (A3A, A3B and A3H haplotype I) have been implicated in somatic mutagenesis.The APOBEC3 enzymes that restrict HIV replication function optimally in the absence of the HIV viral infectivity factor (Vif). Vif targets APOBEC3 for degradation via the proteasome in HIV infected cells. For APOBEC3s that are able to fortuitously escape Vif mediated degradation and become encapsidated, the enzymes can deaminate cytosines to form uracils in viral (-)DNA. Replication of (-)DNA to (+)DNA causes HIV-1 reverse transcriptase to incorporate adenines opposite uracils which creates C/G→T/A transition mutations. While restriction of HIV most commonly occurs through this deamination-dependent mechanism, APOBEC3s have also been identified to interfere with HIV reverse transcriptase processes in a deamination-independent manner, although this mechanism is secondary to the deaminationdependent mode. In order to restrict retroelements and viruses such as HIV, the A3 enzymes iii require an efficient processive ssDNA scanning mechanism that allows them to search for, and locate cytosines on ssDNA in the finite amount of time the substrate is available during formation of the double-stranded DNA provirus. To understand if this requirement was lost in A3 enzymes unable to restrict HIV, we studied A3C. Human A3C is not able to restrict HIV, in comparison to the more active gorilla and chimpanzee A3C orthologs that can restrict HIV, however an explanation for this difference was lacking. A polymorphism, S188I, in human A3C, which is found in less than 3% of the global population lead...

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Section: Role Of Apobec In Somatic Mutagenesismentioning

confidence: 99%

Biochemical Basis of APOBEC3 Deoxycytidine Deaminase Activity on Diverse DNA Substrates

2018

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“…Studies show that different OB folds can bind and establish protein-DNA, protein-RNA and proteinprotein interactions (Arcus, 2002;Agrawal & Kishan, 2003;Theobald et al, 2003). Among these, the interaction of OB fold with ssDNA is most extensively studied and characterized (Theobald et al, 2003;Dickey & Wuttke, 2014;Bhattacharjee et al, 2016;Wu et al, 2016;Gu et al, 2017;Shastrula et al, 2017).…”

Section: Features and Superfamily Division Of Ob Fold Proteinsmentioning

confidence: 99%

Sequence, structure and evolutionary analysis of cold shock domain proteins, a member of OB fold family

Amir

Kumar

Dohare

et al. 2018

J of Evolutionary Biology

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The cold shock domain (CSD) belongs to the oligosaccharide/oligonucleotide‐binding fold superfamily which is highly conserved from prokaryotes to higher eukaryotes, and appears to function as RNA chaperones. CSD is involved in diverse cellular processes, including adaptation to low temperatures, nutrient stress, cellular growth and developmental processes. Structural Classification of Proteins (SCOP) database broadly classifies OB fold proteins into 18 different superfamilies, including nucleic acid‐binding superfamily (NAB). The NAB is further divided into 17 families together with cold shock DNA‐binding protein family (CSDB). The CSDB have more than 240 000 sequences in UniProt database consisting of 32 domains including CSD. Among these domains, CSD is the second largest sequence contributor (> 40 398 sequences). Herein, we have systematically analysed the relative abundance and distribution of CSD proteins based on sequences, structures, repeats and gene ontology (GO) molecular functions in all domains of life. Analysis of sequence distribution suggesting that CSDs are largely found in bacteria (83–94%) with single CSD repeat. However, repeat distribution in eukaryota varies from 1 to 5 in combination with other auxiliary domain that makes CSD proteins functionally more diverse compared to the bacterial counterparts. Further, analysis of repeats distributions on evolutionary scale suggest that existence of CSD in multiple repeats is mainly driven through speciation, gene shuffling and gene duplication events.

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“…Fork stability is maintained by diverse ssDNAbinding proteins, including Replication Protein A (RPA), the recombinase RAD51, and RADX. Together, these proteins regulate replication mechanisms to maintain genome stability at stalled replication forks (5,6).…”

Section: Introductionmentioning

confidence: 99%

RADX condenses single-stranded DNA to antagonize RAD51 loading

Zhang

Schaub

Finkelstein

2020

Preprint

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RADX is a mammalian single-stranded DNA-binding protein that stabilizes telomeres and stalled replication forks. Cellular biology studies have shown that the balance between RADX and Replication Protein A (RPA) activities is critical for DNA replication integrity. RADX is also a negative regulator of RAD51-mediated homologous recombination at stalled forks. However, the mechanism of RADX acting on DNA and its interactions with RPA and RAD51 are enigmatic. Using singlemolecule imaging of the key proteins in vitro, we reveal that RADX condenses ssDNA filaments, even when the ssDNA is coated with RPA at physiological protein ratios. RADX compacts RPA-coated ssDNA filaments via higher-order assemblies that can capture ssDNA in trans. Furthermore, RADX blocks RPA displacement by RAD51 and prevents RAD51 loading on ssDNA.Our results indicate that RADX is an ssDNA condensation protein that inhibits RAD51 filament formation and may antagonize other ssDNA-binding proteins on RPA-coated ssDNA.

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Human single-stranded DNA binding proteins: guardians of genome stability

Cited by 46 publications

References 116 publications

Biochemical Basis of APOBEC3 Deoxycytidine Deaminase Activity on Diverse DNA Substrates

Biochemical Basis of APOBEC3 Deoxycytidine Deaminase Activity on Diverse DNA Substrates

Sequence, structure and evolutionary analysis of cold shock domain proteins, a member of OB fold family

RADX condenses single-stranded DNA to antagonize RAD51 loading

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