The Structure and Function of Replication Protein A in DNA Replication

Prakash, Aishwarya; Borgstahl, Gloria E. O.

doi:10.1007/978-94-007-4572-8_10

Cited by 26 publications

(30 citation statements)

References 134 publications

(145 reference statements)

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“…RPA is the predominant ssDNA-binding moiety in vertebrates, homologous to bacterial SSB protein (Prakash and Borgstahl 2012). In this role, RPA participates as a chaperone for and protector of ssDNA intermediates within a number of different DNAmetabolic processes including HR, nucleotide excision repair (NER), resolution of stalled replication forks (RFs), and lagging strand synthesis during DNA replication.…”

Section: Holding Out: Ncl Sequesters Rpa Away From the Replication Anmentioning

confidence: 99%

Nucleolin and nucleophosmin: nucleolar proteins with multiple functions in DNA repair

Scott

Oeffinger

2016

Biochem. Cell Biol.

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The nucleolus represents a highly multifunctional intranuclear organelle in which, in addition to the canonical ribosome assembly, numerous processes such as transcription, DNA repair and replication, the cell cycle and apoptosis are coordinated. The nucleolus is further a key hub in the sensing of cellular stress and undergoes major structural and compositional changes in response to cellular perturbations.Numerous nucleolar proteins have been identified that, upon nucleolar stress sensing, deploy additional, non-ribosomal roles in the regulation of varied cell processes including cell cycle arrest, arrest of DNA replication, induction of DNA repair, and apoptosis, among others. The highly abundant proteins nucleophosmin (NPM1) and nucleolin (NCL) are two such factors that transit to the nucleoplasm in response to stress, and participate directly in the repair of numerous different DNA damages. This review discusses the contributions made by NCL and/or NPM1 to the different DNA repair pathways employed by mammalian cells to repair DNA insults, and examines the implications of such activities for the regulation, pathogenesis and therapeutic targeting of NPM1 and NCL.

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Section: Holding Out: Ncl Sequesters Rpa Away From the Replication Anmentioning

confidence: 99%

Nucleolin and nucleophosmin: nucleolar proteins with multiple functions in DNA repair

Scott

Oeffinger

2016

Biochem. Cell Biol.

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“…RPA, a single-stranded DNA-binding protein in eukaryotes, binds to ssDNA regions at replication forks. Besides protecting ssDNA regions, RPA coordinates biochemical reactions at forks (35). Dna2 is required for processing Okazaki fragments for the synthesis of lagging strand DNA (36).…”

Section: Cdc24 Functions In Long-range End Resectionmentioning

confidence: 99%

Cdc24 Is Essential for Long-range End Resection in the Repair of Double-stranded DNA Breaks

Zhang¹,

Yu²,

Li³

et al. 2016

Journal of Biological Chemistry

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Edited by Patrick SungDouble-stranded DNA breaks (DSBs) are highly detrimental DNA lesions, which may be repaired by the homologous recombination-mediated repair pathway. The 5 to 3 direction of long-range end resection on one DNA strand, in which 3-single-stranded DNA overhangs are created from broken DNA ends, is an essential step in this pathway. Dna2 has been demonstrated as an essential nuclease in this event, but the molecular mechanism of how Dna2 is recruited to DNA break sites in vivo has not been elucidated. In this study, a novel recombination factor called Cdc24 was identified in fission yeast. We demonstrated that Cdc24 localizes to DNA break sites during the repair of DNA breaks and is an essential factor in long-range end resection. We also determined that Cdc24 plays a direct role in recruiting Dna2 to DNA break sites through its interaction with Dna2 and replication protein A (RPA). Further, this study revealed that RPA acts as the foundation for assembling the machinery for long-range end resection by its essential role in recruiting Cdc24 and Dna2 to DNA break sites. These results define Cdc24 as an essential factor for long-range end resection in the repair of DSBs, opening the door for further investigations into the enzymes involved in long-range end resection for DSB repair. Double-stranded DNA breaks (DSBs) 2 are one of the most cytotoxic DNA lesions. DSBs can occur naturally inside cells (e.g. meiotic recombination, mating type switch, or V(D)J exchange); they can also be caused by endogenous reactive metabolites and extracellular agents (e.g. UV, IR, and chemical agents such as camptothecin (CPT)) (1). If DSBs are left unrepaired or are repaired inappropriately, it will lead to a variety of mutations such as deletions, insertions, translocation, and genetic fusions, resulting in drastic genomic instability (2, 3).Eukaryotic cells have two major and conserved pathways to repair DSBs: non-homologous end joining (NHEJ) and homologous recombination (HR) (4). In NHEJ, two broken DNA ends are rejoined by the concerted actions of Ku70/80, DNAPKcs, DNA ligase IV, and some other proteins and enzymes (5). NHEJ does not need a homologous DNA sequence for the repair of DSBs, so it can occur in any phase of the cell cycles but dominates at G 0 /G 1 (6). Compared with HR, NHEJ is an errorprone pathway because genetic deletion or insertion of a few base pairs is frequently observed at the break-rejoining site (7,8). HR requires a homologous DNA template that is present in a sister chromatid or an ectopic DNA sequence to fix breaks. Therefore, the HR pathway dominates at the S and G 2 phases and is a relatively error-free repair pathway, although genetic mutations can occur at times (9, 10). A central step in the HR pathway is the 5Ј to 3Ј digestion on one DNA strand from broken DNA ends to generate 3Ј-ended single-stranded DNA (ssDNA) overhangs, a process termed DNA end resection (11,12). The HR-mediated repair of DSBs is reliant on this end resection because only ssDNA is able to invade a homologou...

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“…p65 binds the TER activating domain [stem-loop 4 (SL4)], inducing a large bend in the RNA that facilitates assembly of TERT with TER to form the RNP catalytic core ( 33, 34 ). Teb1 is a paralog of human RPA70, the large subunit of RPA ( 16, 28 ). Direct single-stranded telomere DNA binding by Teb1 is necessary for telomerase recruitment to telomeres ( 27 ), where it may compete for binding with the Tetrahymena telomere end-binding Pot1a ( 35 ).…”

mentioning

confidence: 99%

Structure of Tetrahymena telomerase reveals previously unknown subunits, functions, and interactions

Jiang

Chan

Cash

et al. 2015

Science

136

243

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Telomerase helps maintain telomeres by processive synthesis of telomere repeat DNA at their 3′-ends, using an integral telomerase RNA (TER) and telomerase reverse transcriptase (TERT). We report the cryo–electron microscopy structure of Tetrahymena telomerase at ~9 angstrom resolution. In addition to seven known holoenzyme proteins, we identify two additional proteins that form a complex (TEB) with single-stranded telomere DNA-binding protein Teb1, paralogous to heterotrimeric replication protein A (RPA). The p75-p45-p19 subcomplex is identified as another RPA-related complex, CST (CTC1-STN1-TEN1). This study reveals the paths of TER in the TERT-TER-p65 catalytic core and single-stranded DNA exit; extensive subunit interactions of the TERT essential N-terminal domain, p50, and TEB; and other subunit identities and structures, including p19 and p45C crystal structures. Our findings provide structural and mechanistic insights into telomerase holoenzyme function.

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The Structure and Function of Replication Protein A in DNA Replication

Cited by 26 publications

References 134 publications

Nucleolin and nucleophosmin: nucleolar proteins with multiple functions in DNA repair

Nucleolin and nucleophosmin: nucleolar proteins with multiple functions in DNA repair

Cdc24 Is Essential for Long-range End Resection in the Repair of Double-stranded DNA Breaks

Structure of Tetrahymena telomerase reveals previously unknown subunits, functions, and interactions

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