Human HLTF mediates postreplication repair by its HIRAN domain-dependent replication fork remodelling

Achar, Yathish Jagadheesh; Balogh, D.; Neculai, Dante; Juhász, Szilvia; Mórocz, Mónika; Gali, Himabindu; Dhe‐Paganon, Sirano; Venclovas, C̆eslovas; Haracska, Lajos

doi:10.1093/nar/gkv896

Cited by 52 publications

(105 citation statements)

References 47 publications

(66 reference statements)

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“…HLTF reverses replication forks either lacking any ssDNA or containing a gap on the leading strand in a process dependent on the ATPase domain and ATP hydrolysis (Blastyak et al , 2010, Achar et al , 2011, Achar et al , 2015, Kile et al , 2015). However, studies with other DNA substrates, such as lagging strand gapped substrates, have not been reported.…”

Section: Hltfmentioning

confidence: 99%

“…In addition to being present in HTLF and Rad5, the HIRAN domain is found as a stand-alone protein in some prokaryotic organisms and linked to other functional domains in some eukaryotes (Iyer et al , 2006). The HIRAN domain is required for DNA binding and fork remodeling catalyzed by HLTF but is dispensable for the ubiquitin ligase activity (Achar et al , 2015, Kile et al , 2015). In contrast to the HARP and HARP-like domains of SMARCAL1 and ZRANB3, the HIRAN domain of HLTF is not required for efficient DNA-dependent ATP hydrolysis (Kile et al , 2015).…”

Section: Hltfmentioning

confidence: 99%

“…The HIRAN domain by itself recognizes ssDNA overhangs with a preference for 3′ overhangs (Hishiki et al , 2015, Kile et al , 2015). High-resolution structural studies of the HIRAN domain in HLTF indicate the structure of this domain is strongly conserved throughout evolution (Achar et al , 2015, Hishiki et al , 2015, Kile et al , 2015, Korzhnev et al , 2016). Studies performed in the presence of DNA show that the HIRAN domain recognizes a 3′-hydroxyl group (3′OH) (Hishiki et al , 2015, Kile et al , 2015).…”

Section: Hltfmentioning

confidence: 99%

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Functions of SMARCAL1, ZRANB3, and HLTF in maintaining genome stability

Poole

Chen

2017

Critical Reviews in Biochemistry and Molecular Biology

115

104

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A large number of SNF2 family, DNA and ATP-dependent motor proteins are needed during transcription, DNA replication, and DNA repair to manipulate protein-DNA interactions and change DNA structure. SMARCAL1, ZRANB3, and HLTF are three related members of this family with specialized functions that maintain genome stability during DNA replication. These proteins are recruited to replication forks through protein-protein interactions and bind DNA using both their motor and substrate recognition domains (SRD). The SRD provides specificity to DNA structures like forks and junctions and confer DNA remodeling activity to the motor domains. Remodeling reactions include fork reversal and branch migration to promote fork stabilization, template switching, and repair. Regulation ensures these powerful activities remain controlled and restricted to damaged replication forks. Inherited mutations in SMARCAL1 cause a severe developmental disorder and mutations in ZRANB3 and HLTF are linked to cancer illustrating the importance of these enzymes in ensuring complete and accurate DNA replication. In this review, we examine how these proteins function, concentrating on their common and unique attributes and regulatory mechanisms.

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Section: Hltfmentioning

confidence: 99%

Section: Hltfmentioning

confidence: 99%

Section: Hltfmentioning

confidence: 99%

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Functions of SMARCAL1, ZRANB3, and HLTF in maintaining genome stability

Poole

Chen

2017

Critical Reviews in Biochemistry and Molecular Biology

115

104

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“…Several enzymes have been shown to exhibit fork reversal activity, including the DNA helicases FBH1, BLM, WRN and RECQL5 and the DNA translocases RAD54, FANCM, HLTF, SMARCAL1 and ZRANB3 (Betous et al, 2013; Betous et al, 2012; Blastyak et al, 2010; Ciccia et al, 2012; Kile et al, 2015; Neelsen and Lopes, 2015). SMARCAL1, ZRANB3 and HLTF are SNF2-family members that catalyze fork remodeling by similar mechanisms of action (Achar et al, 2015; Badu-Nkansah et al, 2016; Betous et al, 2013; Betous et al, 2012; Blastyak et al, 2010; Ciccia et al, 2012; Kile et al, 2015). SMARCAL1 and ZRANB3 are recruited to sites of replication fork stalling by the ssDNA-binding complex RPA and the polyubiquitinated form of the DNA polymerase clamp PCNA, respectively (Bansbach et al, 2009; Ciccia et al, 2009; Ciccia et al, 2012; Postow et al, 2009; Weston et al, 2012; Yuan et al, 2009, 2012; Yusufzai et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Restoration of Replication Fork Stability in BRCA1- and BRCA2-Deficient Cells by Inactivation of SNF2-Family Fork Remodelers

et al. 2017

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SUMMARY To ensure the completion of DNA replication and maintenance of genome integrity, DNA repair factors protect stalled replication forks upon replication stress. Previous studies have identified a critical role for the tumor suppressors BRCA1 and BRCA2 in preventing the degradation of nascent DNA by the MRE11 nuclease after replication stress. Here we show that depletion of SMARCAL1, a SNF2-family DNA translocase that remodels stalled forks, restores replication fork stability and reduces the formation of replication stress-induced DNA breaks and chromosomal aberrations in BRCA1/2-deficient cells. In addition to SMARCAL1, other SNF2-family fork remodelers, including ZRANB3 and HLTF, cause nascent DNA degradation and genomic instability in BRCA1/2-deficient cells upon replication stress. Our observations indicate that nascent DNA degradation in BRCA1/2-deficient cells occurs as a consequence of MRE11-dependent nucleolytic processing of reversed forks generated by fork remodelers. These studies provide mechanistic insights into the processes that cause genome instability in BRCA1/2-deficient cells.

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“…The SRD in HLTF is its HIRAN domain, which is unrelated in sequence and structure to the HARP domain and interacts with the exposed 3Ј end of small DNA flaps (19 -21). The HIRAN domain is also important for HLTF mediated fork regression activity (19,22). In both SMARCAL1 and HLTF, mutations in the HARP or HIRAN domains interfere with their ability to bind DNA (4, 19 -21).…”

mentioning

confidence: 99%

Identification of a Substrate Recognition Domain in the Replication Stress Response Protein Zinc Finger Ran-binding Domain-containing Protein 3 (ZRANB3)

Badu-Nkansah

Mason

Eichman

et al. 2016

Journal of Biological Chemistry

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DNA damage and other forms of replication stress can cause replication forks to stall. Replication stress response proteins stabilize and resolve stalled forks by mechanisms that include fork remodeling to facilitate repair or bypass of damaged templates. Several enzymes including SMARCAL1, HLTF, and ZRANB3 catalyze these reactions. SMARCAL1 and HLTF utilize structurally distinct accessory domains attached to an ATPase motor domain to facilitate DNA binding and catalysis of fork remodeling reactions. Here we describe a substrate recognition domain within ZRANB3 that is needed for it to recognize forked DNA structures, hydrolyze ATP, catalyze fork remodeling, and act as a structure-specific endonuclease. Thus, substrate recognition domains are a common feature of fork remodeling, SNF2-family, DNA-dependent ATPases, and our study provides further mechanistic understanding of how these enzymes maintain genome integrity during DNA replication.Genomic replication is a highly challenging task. The DNA replication machinery must precisely duplicate billions of base pairs while tolerating a multitude of obstacles including damaged DNA, collisions with transcriptional machineries, unusual DNA structures, and other difficult to replicate sequences (1). Many of these obstacles stall replication forks and activate replication stress responses that stabilize and restart persistently stalled forks. These mechanisms include fork remodeling to regress replication forks into a chicken foot DNA structure (2, 3). Fork regression may facilitate DNA repair or template switching to bypass the obstruction (3).Several members of the SNF2 family of DNA-dependent ATPases including SMARCAL1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1), 3 HLTF (helicase-like transcription factor) and ZRANB3 (zinc finger Ran-binding domain containing 3) are replication stress response proteins that catalyze fork remodeling including fork regression (4 -6). The replication stress response is essential to complete replication accurately. Therefore, defects in this response cause human disease (1). For example, bi-allelic loss of function mutations in SMARCAL1 cause Schimke-Immunoosseous Dysplasia (SIOD) (7). SIOD is a developmental disorder characterized by growth defects, immune-deficiency, and renal failure. Recent studies also suggest that SIOD may be a cancer predisposition syndrome (8 -10). HLTF is silenced in colorectal cancer and ZRANB3 is mutated in endometrial cancers suggesting that both may be tumor suppressors (11,12). SMARCAL1 localizes to stalled replication forks through an interaction with RPA (13-16). The RPA interaction also regulates SMARCAL1 enzymatic activity to ensure that it regresses only stalled forks (17, 18). Although HLTF is present at replication forks, it is unclear if it is recruited through a protein-protein interaction or simply by its structure-specific DNA binding activity (19). ZRANB3 is recruited by binding to poly-ubiquitinated PCNA (5).The enzymatic activities of S...

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Human HLTF mediates postreplication repair by its HIRAN domain-dependent replication fork remodelling

Cited by 52 publications

References 47 publications

Functions of SMARCAL1, ZRANB3, and HLTF in maintaining genome stability

Functions of SMARCAL1, ZRANB3, and HLTF in maintaining genome stability

Restoration of Replication Fork Stability in BRCA1- and BRCA2-Deficient Cells by Inactivation of SNF2-Family Fork Remodelers

Identification of a Substrate Recognition Domain in the Replication Stress Response Protein Zinc Finger Ran-binding Domain-containing Protein 3 (ZRANB3)

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