Structure-Specific Endonucleases Xpf and Mus81 Play Overlapping but Essential Roles in DNA Repair by Homologous Recombination

Kikuchi, Koji; Narita, Takeo; Pham, Van T.; Iijima, Junko; Hirota, Kouji; Keka, Islam Shamima; Mohiuddin, Mohiuddin; Okawa, Katsuya; Hori, Tomohide; Fukagawa, Tatsuo; Essers, Jeroen; Kanaar, Roland; Whitby, Matthew C.; Sugasawa, Kaoru; Taniguchi, Yoshihito; Kitagawa, Katsumi; Takeda, Shunichi

doi:10.1158/0008-5472.can-12-3154

Cited by 31 publications

(36 citation statements)

References 49 publications

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“…We were unable to construct a double mutant between rad16-249 and mus81Δ (Table 1); this synthetic lethality suggests that lesions produced in mus81Δ mutants in vegetative growth absolutely depend upon Rad16 for resolution and vice versa. This is consistent with data suggesting that Rad16 and Mus81 overlap to maintain genome stability in metazoans (Mazon et al 2012;Muñoz-Galván et al 2012;Kikuchi et al 2013;Saito et al 2013). In vegetative fission yeast cells, Rad16 functions as a template specific resolvase during repair of replication forks, along with Mus81 (Roseaulin et al 2008).…”

Section: Rad16-249 Has Genetic Interactions With Other Dna Damage Repsupporting

confidence: 91%

“…Structure-specific endonucleases such as Mus81 and XPF actively contribute to recombination events that rescue damaged replication forks or other structures, thus promoting genome stability (e.g., Roseaulin et al 2008;Willis and Rhind 2009;Muñoz-Galván et al 2012). The synthetic lethality we observe between rad16-249 and mus81Δ is consistent with data in metazoans that argues for redundancy between these two enzymes, with deficiency leading to increased double strand DNA breaks (Kikuchi et al 2013). Yet these same proteins contribute actively to gross chromosome rearrangements, including translocations, which are typical of cancer (Mazon et al 2012;Pardo and Aguilera 2012).…”

Section: Genome Instability In Vegetative Rad16 Cellssupporting

confidence: 86%

“…Despite this, mammalian XPF is not essential for viability (Brookman et al 1996;Tian et al 2004), possibly because it overlaps with another structure-specific endonuclease, Mus81. In chicken DT40 cells that lack Mus81, XPF is essential for viability and inactivation leads to chromosome breakage and failure at a late stage of HR (Kikuchi et al 2013). Mammalian XPF is also implicated in telomere protection (Zhu et al 2003;Muñoz et al 2005).…”

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confidence: 99%

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Increased Meiotic Crossovers and Reduced Genome Stability in Absence of Schizosaccharomyces pombe Rad16 (XPF)

Mastro¹,

Forsburg

2014

Genetics

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Schizosaccharomyces pombe Rad16 is the ortholog of the XPF structure-specific endonuclease, which is required for nucleotide excision repair and implicated in the single strand annealing mechanism of recombination. We show that Rad16 is important for proper completion of meiosis. In its absence, cells suffer reduced spore viability and abnormal chromosome segregation with evidence for fragmentation. Recombination between homologous chromosomes is increased, while recombination within sister chromatids is reduced, suggesting that Rad16 is not required for typical homolog crossovers but influences the balance of recombination between the homolog and the sister. In vegetative cells, rad16 mutants show evidence for genome instability. Similar phenotypes are associated with mutants affecting Rhp14 XPA but are independent of other nucleotide excision repair proteins such as Rad13 XPG . Thus, the XPF/XPA module of the nucleotide excision repair pathway is incorporated into multiple aspects of genome maintenance even in the absence of external DNA damage.T HE XPF/ERCC1 protein complex is one of several structurespecific endonucleases that function broadly as resolvases in the repair of damaged DNA (Schwartz and Heyer 2011). Rad16/Swi9 is the fission yeast ortholog of endonuclease XPF, which forms a complex with Swi10/Rad23 (ERCC1) (Carr et al. 1994). XPF has a conserved role in nucleotide excision repair (NER) to remove UV-induced lesions in the DNA (Camenisch et al. 2006;Gregg et al. 2011). In humans, mutation of XPF is associated with xeroderma pigmentosum (XP), which causes sun sensitivity and high rates of skin cancer, as well as premature aging and neurological disorders (Camenisch et al. 2006;Gregg et al. 2011). Recent studies suggest XPF mutations are also associated with Fanconi anemia (FA), which requires repair of interstrand crosslinks (ICLs) (Bogliolo et al. 2013;Kashiyama et al. 2013). The canonical model for NER suggests that upon recognition of helix-distorting lesions, the DNA is unwound to form a bubble around the damage. XPA (SpRhp14) loads XPF (SpRad16) and ERCC1 (SpSwi10); XPF cleaves at the 59 end of the bubble while XPG (SpRad13), another endonuclease, cleaves at the 39 end to remove the offending segment (Fagbemi et al. 2011;Schwartz and Heyer 2011). Thus, Schizosaccharomyces pombe rad16 mutants show a decrease in (6-4) photoproduct excision (McCready et al. 1993;Carr et al. 1994).Consistent with these clinical effects, XPF is implicated in multiple mechanisms of genome maintenance (Paques and Haber 1997;Gregg et al. 2011;Schwartz and Heyer 2011). XPF is required for single strand annealing (SSA), a form of double strand break (DSB) repair distinct from typical homologous recombination (HR) (Ma et al. 2003;Kass and Jasin 2010). This occurs when short regions of homology exposed by resection are able to pair, leaving nonhomologous 39 overhangs as substrates for XPF cleavage. In budding yeast, recruitment of ScRad1 XPF and ScRad10 ERCC1 in this pathway depends on interactions with other pro...

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Section: Rad16-249 Has Genetic Interactions With Other Dna Damage Repsupporting

confidence: 91%

Section: Genome Instability In Vegetative Rad16 Cellssupporting

confidence: 86%

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confidence: 99%

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Increased Meiotic Crossovers and Reduced Genome Stability in Absence of Schizosaccharomyces pombe Rad16 (XPF)

Mastro¹,

Forsburg

2014

Genetics

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“…Intriguingly, random-integration frequency was more than fivefold higher in RAD54-null cells than in their wild-type counterparts, implying that the observed reduction of gene-targeting efficiency in the absence of Rad54 is due, at least in part, to an unexpectedly increased random-integration frequency. Similar observations were made with mutant cell lines deficient in MUS81 and/or FANCB, genes implicated in HR [45,46] (Figure 1B-D). It is also important to note that the increased random-integration frequency associated with HR deficiency was suppressed by an additional loss of NHEJ, and this suppression was less pronounced when targeting vectors were used ( Figure 1B,C).…”

Section: Impact Of Dsb Repair Deficiency On Targeted and Random Integsupporting

confidence: 84%

Repair of Accidental DNA Double-Strand Breaks in the Human Genome and Its Relevance to Vector DNA Integration

Adachi

Saito²,

Kurosawa³

2014

Gene Technology

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Efficient repair of chromosomal DNA damage is crucial for cells to maintain genome integrity. DNA double-strand breaks (DSBs) are the most severe type of DNA lesions that can be caused by various exogenous and endogenous mechanisms, such as ionizing radiation, reactive oxygen species, topoisomerase poisons, or replication errors [1]. DSBs, if left unrepaired or mis-repaired, lead to cell death or chromosomal aberrations [2,3]. Human cells have evolved two fundamentally different mechanisms for repairing chromosomal DSBs, homologous recombination (HR) and non-homologous end-joining (NHEJ) [4]. NHEJ not only repairs accidental (non-physiological) DSBs, but is also essential for rejoining physiological DSBs that arise in the process of V(D)J recombination in B and T lymphocytes and class switch recombination in mature B cells [3].A wide variety of proteins have been identified thus far that contribute to the HR and NHEJ machineries [5]. HR is a highly complicated process of DNA transaction, in which Rad51 protein plays an essential role in DNA strand exchange with the aid of several other proteins such as Rad54, Brca2, Rad52, and Rad51 paralogs [6,7]. For HR to occur, DSBs should be processed (i.e., end-resected) to produce a long 3'-overhang single-stranded DNA [8,9], and recent studies have identified a number of proteins involved in end resection or its regulation; among these, Mre11 and CtIP play essential roles in the initial step of end resection [9][10][11]. In contrast to HR, NHEJ is thought to be a rather simpler process that requires, at least biochemically, only four proteins (two protein complexes); specifically, Ku, a heterodimer of Ku70 and Ku80, initiates an NHEJ reaction by binding to the ends of a DSB, and the DNA ligase complex composed of Xrcc4 and Ligase IV (Lig4) seals the ends to complete repair [3]. In most cases, however, many other proteins do participate in NHEJ-mediated repair to trim the DSB ends, which are typically non-ligatable or non-compatible. These additional NHEJ factors involve DNA-PKcs, Artemis, XLF, and DNA polymerase µ/λ; DNA-PKcs and Artemis have evolved in higher eukaryotes and do not exist in yeasts [3,12]. In addition to the classical pathway of NHEJ, recent evidence indicates the existence of a more error-prone mechanism of NHEJ called alternative endjoining that plays a role in DSB repair [3,13]. Alternative end-joining is Ku/Lig4 independent and the precise mechanism remains largely unclear, although PARP1, Ligase III, and several factors involved in end resection (to initiate HR) have been implicated in DSB repair via alternative end-joining [14][15][16].Which DSB repair pathway is beneficial for cells to preserve genome integrity? NHEJ (the classical NHEJ pathway) repairs broken DNA ends with little or no homology and is often associated with nucleotide loss, whereas HR allows for accurate repair of DSBs with the use of homologous DNA sequence, usually located on a sister chromatid [3,4,12]. Such difference in accuracy between the two pathways, however, does not mean...

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“…The 5′-3′ structure-specific endonuclease activity of the complex was subsequently shown to be also required for the Fanconi anemia (FA) pathway of interstrand crosslink repair (ICL-R), [1][2][3] as well as for homology-directed repair (HDR) of DNA double-strand breaks (DSB). [4][5][6][7] XPF is catalytically active, while ERCC1 tethers the activity of the complex to the site of repair through physical interactions with the core machinery complexes of several repair pathways (see ref. 8 for review).…”

Section: Introductionmentioning

confidence: 99%

ERCC1 function in nuclear excision and interstrand crosslink repair pathways is mediated exclusively by the ERCC1-202 isoform

Friboulet

Postel-Vinay²,

Sourisseau

et al. 2013

Cell Cycle

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Structure-Specific Endonucleases Xpf and Mus81 Play Overlapping but Essential Roles in DNA Repair by Homologous Recombination

Cited by 31 publications

References 49 publications

Increased Meiotic Crossovers and Reduced Genome Stability in Absence of Schizosaccharomyces pombe Rad16 (XPF)

Increased Meiotic Crossovers and Reduced Genome Stability in Absence of Schizosaccharomyces pombe Rad16 (XPF)

Repair of Accidental DNA Double-Strand Breaks in the Human Genome and Its Relevance to Vector DNA Integration

ERCC1 function in nuclear excision and interstrand crosslink repair pathways is mediated exclusively by the ERCC1-202 isoform

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