Mammalian base excision repair by DNA polymerases δ and ε

Stucki, Manuel; Pascucci, Barbara; Parlanti, Eleonora; Fortini, Paola; Wilson, Samuel H.; Hübscher, Ulrich; Dogliotti, Eugenia

doi:10.1038/sj.onc.1202001

Cited by 170 publications

(120 citation statements)

References 24 publications

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“…Repair completion requires a 3'OH moiety for proper nucleotidyl transfer and chain elongation. In cases where the 5'lesion is refractory to pol ß lyase activity [8], polymerase δ, ε or ß, coupled with proliferating cell nuclear antigen (PCNA) and a variety of other proteins including the structure specific flap endonuclease (Fen1), poly(ADP-ribose)polymerase 1 (PARP1) and LigI synthesizes DNA to fill the gap, resulting in a displaced DNA flap of 2-13 bases in length [8][9][10]. DNA synthesis and strand displacement by pol ß is stimulated by the combined presence of Fen1 and PARP1 [11,12].…”

Section: Introduction Of a Unifying Ber Modelmentioning

confidence: 99%

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

Almeida¹,

Sobol²

2007

DNA Repair

379

374

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Base excision repair (BER) proteins act upon a significantly broad spectrum of DNA lesions that result from endogenous and exogenous sources. Multiple sub-pathways of BER (short-path or longpatch) and newly designated DNA repair pathways (e.g., SSBR and NIR) that utilize BER proteins complicate any comprehensive understanding of BER and its role in genome maintenance, chemotherapeutic response, neurodegeneration, cancer or aging. Herein, we propose a unified model of BER, comprised of three functional processes: Lesion Recognition/Strand Scission, Gap Tailoring and DNA Synthesis/Ligation, each represented by one or more multiprotein complexes and coordinated via the XRCC1/DNA Ligase III and PARP1 scaffold proteins. BER therefore may be represented by a series of repair complexes that assemble at the site of the DNA lesion and mediates repair in a coordinated fashion involving protein-protein interactions that dictate subsequent steps or sub-pathway choice. Complex formation is influenced by post-translational protein modifications that arise from the cellular state or the DNA damage response, providing an increase in specificity and efficiency to the BER pathway. In this review, we have summarized the reported BER proteinprotein interactions and protein post-translational modifications and discuss the impact on DNA repair capacity and complex formation.

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Section: Introduction Of a Unifying Ber Modelmentioning

confidence: 99%

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

Almeida¹,

Sobol²

2007

DNA Repair

379

374

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“…In short patch BER, the Pol X family polymerase Pol β fills the 1-nt gap and removes the 5' dRP with its lyase activity [12,13]. In the long patch pathway, either Pol δ or Pol β performs displacement synthesis [14,15], yielding a 5' flap, which is cleaved by FEN-1 (Rad27 in yeast) [16]. Compellingly, Pol4 and Pol β are each nonprocessive gap-filling polymerases, and both have 5' dRP lyase activity [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Evidence that base stacking potential in annealed 3′ overhangs determines polymerase utilization in yeast nonhomologous end joining

Daley

Wilson

2008

DNA Repair

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Nonhomologous end joining (NHEJ) directly rejoins DNA double-strand breaks (DSBs) when recombination is not possible. In Saccharomyces cerevisiae, the DNA polymerase Pol4 is required for gap filling when a short 3' overhang must prime DNA synthesis. Here, we examined further end variations to test specific hypotheses regarding Pol4 usage in NHEJ in vivo. Surprisingly, Pol4 dependence at 3' overhangs was reduced when a nonhomologous 5' flap nucleotide was present across from the gap, even though the mismatched nucleotide was resynthesized, not incorporated. In contrast, a gap with a 5' deoxyribosephosphate (dRP) was as Pol4-dependent as a gap with a 5' phosphate, demonstrating the importance of the downstream base in relaxing the Pol4 requirement. Combined with prior observations of Pol4-independent NHEJ of nicks with 5' hydroxyls, we suggest that base stacking interactions across the broken strands can stabilize a joint, allowing another polymerase to substitute for Pol4. This model predicts that a unique function of Pol4 is to actively stabilize template strands that lack stacking continuity. We also explored whether NHEJ end processing can occur via short and long patch pathways analogous to base excision repair. Results demonstrated that 5' dRPs could be removed in the absence of Pol4 lyase activity. The 5' flap endonuclease Rad27 was not required for repair in this or any situation tested, indicating that still other NHEJ 5' nucleases must exist.

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“…Transcripts encoding seven DNA polymerases or their subunits are expressed at least 4-fold higher in spermatids than in any other testicular cell type and two of these, Polk (DNA-directed polymerase ) and the Pold3 (accessory 3A). Their regulated expression was noteworthy because spermatids have enhanced DNA repair capacity and because Polk and Pold3 participate in nucleotide excision repair and base excision repair, respectively (15)(16)(17). Because preservation of genome integrity is required for male fertility, we sought to gain as complete a picture as possible of the regulation of DNA repair processes in spermatogenic cells.…”

Section: Analysis Of Defined Stages Of the Cycle Of The Seminiferous mentioning

confidence: 99%

Stage-specific gene expression is a fundamental characteristic of rat spermatogenic cells and Sertoli cells

Johnston¹,

Wright

DiCandeloro³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

131

141

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Mammalian spermatogenesis is a complex biological process that occurs within a highly organized tissue, the seminiferous epithelium. The coordinated maturation of spermatogonia, spermatocytes, and spermatids suggests the existence of precise programs of gene expression in these cells and in their neighboring somatic Sertoli cells. The objective of this study was to identify the genes that execute these programs. Rat seminiferous tubules at stages I, II-III, IV-V, VI, VIIa,b, VIIc,d, VIII, IX-XI, XII, and XIII-XIV of the cycle were isolated by microdissection, whereas Sertoli cells, spermatogonia plus early spermatocytes, pachytene spermatocytes, and round spermatids were purified from enzymatically dispersed testes. Microarray analysis by using Rat Genome 230 2.0 arrays identified 16,971 probe sets that recognized testicular transcripts, and 398 of these were identified as testis-specific. Expression of 1,286 probe sets were found to differ at least 4-fold between two cell types and also across the stages of the cycle. Pathway and annotated cluster analyses of those probe sets predicted that entire biological pathways and processes are regulated cyclically in specific cells. Important among these are the cell cycle, DNA repair, and embryonic neuron development. Taken together, these data indicate that stage-regulated gene expression is a widespread and fundamental characteristic of spermatogenic cells and Sertoli cells.array analysis ͉ spermatogenesis ͉ seminiferous tubules ͉ stages of the cycle of the seminiferous epithellum ͉ contraception I n mammals, spermatogenesis encompasses a series of precisely timed cellular events that take place in a highly organized tissue, the seminiferous epithelium. Within each cross-section of this tissue, spermatogonia, spermatocytes, and spermatids are in intimate physical association with somatic Sertoli cells, and, together, these cells progress synchronously through the stages of the cycle of the seminiferous epithelium (1, 2). Four cycles are required for spermatogonia, and their progeny to complete spermatogenesis. The synchrony of germ cell development has a significant effect on the structures and functions of both the germ cells and their associated somatic Sertoli cells, suggesting the existence of precise and coordinated cyclic programs of gene expression. However, because investigators have evaluated the stage-dependent changes in expression of only a few genes, whether or not cyclic gene expression is a rare or prevalent characteristic of these cells is unknown (3-7). It is also not known whether genes encoding components of important biological pathways and processes are coordinately regulated in a cyclic manner. However, such genes may represent new targets for the development of male contraceptives.Given the coordinated nature of spermatogenesis, we hypothesized that the expression of large numbers of genes differ substantially, both between specific cell types within the seminiferous epithelium and within a given cell type as it progresses through the stages of...

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Mammalian base excision repair by DNA polymerases δ and ε

Cited by 170 publications

References 24 publications

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

Evidence that base stacking potential in annealed 3′ overhangs determines polymerase utilization in yeast nonhomologous end joining

Stage-specific gene expression is a fundamental characteristic of rat spermatogenic cells and Sertoli cells

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