Structure of a Novel DNA-binding Domain of Helicase-like Transcription Factor (HLTF) and Its Functional Implication in DNA Damage Tolerance

Hishiki, Asami; Hara, Kodai; Ikegaya, Yuzu; Yokoyama, Hideshi; Shimizu, Toshiyuki; Sato, Mamoru; Hashimoto, Hiroshi

doi:10.1074/jbc.m115.643643

Cited by 70 publications

(100 citation statements)

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“…HLTF is a DNA translocase involved in postreplication DNA repair occurring in the S phase of the cycle (49,(72)(73)(74). As such, it has been mostly studied in dividing cells, in which DNA repair processes are important to avoid aberrant DNA synthesis that would be a source of mutations or DSBs.…”

Section: Resultsmentioning

confidence: 99%

HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages

Lahouassa

Blondot

Chauveau

et al. 2016

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

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Viruses often interfere with the DNA damage response to better replicate in their hosts. The human immunodeficiency virus 1 (HIV-1) viral protein R (Vpr) protein has been reported to modulate the activity of the DNA repair structure-specific endonuclease subunit (SLX4) complex and to promote cell cycle arrest. Vpr also interferes with the base-excision repair pathway by antagonizing the uracil DNA glycosylase (Ung2) enzyme. Using an unbiased quantitative proteomic screen, we report that Vpr down-regulates helicase-like transcription factor (HLTF), a DNA translocase involved in the repair of damaged replication forks. Vpr subverts the DDB1-cullin4-associatedfactor 1 (DCAF1) adaptor of the Cul4A ubiquitin ligase to trigger proteasomal degradation of HLTF. This event takes place rapidly after Vpr delivery to cells, before and independently of Vpr-mediated G2 arrest. HLTF is degraded in lymphocytic cells and macrophages infected with Vpr-expressing HIV-1. Our results reveal a previously unidentified strategy for HIV-1 to antagonize DNA repair in host cells.HIV | restriction factor | DNA repair | Vpr target | SILAC

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Section: Resultsmentioning

confidence: 99%

HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages

Lahouassa

Blondot

Chauveau

et al. 2016

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

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“…SMARCAL1, ZRANB3, and HLTF all have an SNF2-type ATPase domain but differ in the accessory domains needed for DNA binding and activity. A HARP domain in SMARCAL1 is thought to mediate structure-specific DNA binding, whereas a HIRAN domain in HLTF recognizes the 3′ end of DNA strands (3,12,23). High-resolution structures indicate that these domains are distinct even though biochemically they both may serve to link the ATPase motor domains to specific substrates and reactions (12,24).…”

mentioning

confidence: 99%

“…A HARP domain in SMARCAL1 is thought to mediate structure-specific DNA binding, whereas a HIRAN domain in HLTF recognizes the 3′ end of DNA strands (3, 12, 23). High-resolution structures indicate that these domains are distinct even though biochemically they both may serve to link the ATPase motor domains to specific substrates and reactions (12,24). As yet, the structure of the ZRANB3 accessory domain is unknown, although it has been postulated to resemble a HARP domain (10).…”

mentioning

confidence: 99%

SMARCAL1 maintains telomere integrity during DNA replication

Poole

Zhao

Glick

et al. 2015

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

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The SMARCAL1 (SWI/SNF related, matrix-associated, actin-dependent, regulator of chromatin, subfamily A-like 1) DNA translocase is one of several related enzymes, including ZRANB3 (zinc finger, RAN-binding domain containing 3) and HLTF (helicase-like transcription factor), that are recruited to stalled replication forks to promote repair and restart replication. These enzymes can perform similar biochemical reactions such as fork reversal; however, genetic studies indicate they must have unique cellular activities. Here, we present data showing that SMARCAL1 has an important function at telomeres, which present an endogenous source of replication stress. SMARCAL1-deficient cells accumulate telomere-associated DNA damage and have greatly elevated levels of extrachromosomal telomere DNA (C-circles). Although these telomere phenotypes are often found in tumor cells using the alternative lengthening of telomeres (ALT) pathway for telomere elongation, SMARCAL1 deficiency does not yield other ALT phenotypes such as elevated telomere recombination. The activity of SMARCAL1 at telomeres can be separated from its genome-maintenance activity in bulk chromosomal replication because it does not require interaction with replication protein A. Finally, this telomere-maintenance function is not shared by ZRANB3 or HLTF. Our results provide the first identification, to our knowledge, of an endogenous source of replication stress that requires SMARCAL1 for resolution and define differences between members of this class of replication fork-repair enzymes.SMARCAL1 | telomere | replication stress | c-circle T he complete and accurate duplication of the genome in each cell-division cycle is challenged by many sources of replication stress including DNA template damage, collisions between replication and transcriptional machineries, and difficult-to-replicate DNA sequences. To overcome these challenges, cells use a multifaceted replication stress response that includes specialized enzymes that stabilize, repair, and restart stalled replication forks.Among these enzymes are members of the SNF2 family of DNA-dependent ATPases that include SMARCAL1 (SWI/SNF related, matrix-associated, actin-dependent, regulator of chromatin, subfamily A-like 1), ZRANB3 (zinc finger, RAN-binding domain containing 3), and HLTF (helicase-like transcription factor) (1). These DNA translocases bind replication fork structures, hydrolyze ATP, and perform branch migration reactions (2-11). Each of these enzymes can catalyze fork regression in vitro, although it is still unclear whether they perform this reaction in vivo (3, 4, 6-8, 11, 12). SMARCAL1 and ZRANB3 also can catalyze DNA strand annealing, disrupt displacement loop structures, and catalyze fork restoration reactions to return a regressed fork back into a normal fork structure (3,4,13).Given the overlapping biochemical activities among these translocases, it is unclear why the cell employs so many different enzymes at stalled forks. Genetic studies indicate these proteins have distinct functions. HLTF ...

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“…E3 ubiquitin-protein ligase RAD18, which is involved in the post-replication repair of UV-damaged DNA, and helicase-like transcription factor, which functions in the error-free post-replication repair of damaged DNA and the maintenance of genomic stability (53). HLTF is a SWI2/SNF2-family ATP-dependent chromatin remodeling enzyme that acts in the error-free branch of DNA damage tolerance (DDT), a cellular mechanism that enables replication of damaged DNA while leaving damage repair for a later time (54). Alterations in the expression levels of these genes may affect the cellular DNA damage repair capacity.…”

Section: Fold Change ------------------------------------------------mentioning

confidence: 99%