SMARCAL1 deficiency predisposes to non‐Hodgkin lymphoma and hypersensitivity to genotoxic agents in vivo

Baradaran‐Heravi, Alireza; Raams, Anja; Lubieniecka, Joanna M.; Cho, Kyoung Sang; DeHaai, Kristi A.; Basiratnia, Mitra; Mari, Pierre-Olivier; Xue, Yutong; Rauth, Michael; Olney, Ann Haskins; Shago, Mary; Choi, Kunho; Weksberg, Rosanna; Nowaczyk, Małgorzata J.M.; Wang, Weidong; Jaspers, Nicolaas G. J.; Boerkoel, Cornelius F.

doi:10.1002/ajmg.a.35532

Cited by 35 publications

(33 citation statements)

References 36 publications

(74 reference statements)

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“…SMARCAL1 deficiency causes the SIOD human disease, which is associated with immune deficiency (84). This observation, together with our finding that HLTF is antagonized by a viral protein, may suggest that these DNA translocases could play a role in the immune defense against pathogens.…”

Section: Resultsmentioning

confidence: 54%

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: 54%

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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“…Marcal1 mutant flies were also sensitive to killing by camptothecin (CPT), similar to both mouse and human cell studies (Baradaran-Heravi et al 2012b). CPT prevents topoisomerase I from religating DNA after it has nicked a strand and become covalently bound to the end (Pommier et al 2010).…”

Section: Marcal1 Mutants Show Elevated Lethality When Exposed To Dsb-mentioning

confidence: 58%

“…SIOD patients have multiple clinical features, some of which are similar to those of DNA damage-repair disorders such as Bloom syndrome and Fanconi anemia. These include poor growth, immune deficiencies, and premature aging symptoms (Lou et al 2002;Baradaran-Heravi et al 2012b;Morimoto et al 2016).…”

mentioning

confidence: 99%

Annealing of Complementary DNA Sequences During Double-Strand Break Repair inDrosophilaIs Mediated by the Ortholog of SMARCAL1

Holsclaw

Sekelsky

2017

Genetics

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DNA double-strand breaks (DSBs) pose a serious threat to genomic integrity. If unrepaired, they can lead to chromosome fragmentation and cell death. If repaired incorrectly, they can cause mutations and chromosome rearrangements. DSBs are repaired using end-joining or homology-directed repair strategies, with the predominant form of homology-directed repair being synthesisdependent strand annealing (SDSA). SDSA is the first defense against genomic rearrangements and information loss during DSB repair, making it a vital component of cell health and an attractive target for chemotherapeutic development. SDSA has also been proposed to be the primary mechanism for integration of large insertions during genome editing with CRISPR/Cas9. Despite the central role for SDSA in genome stability, little is known about the defining step: annealing. We hypothesized that annealing during SDSA is performed by the annealing helicase SMARCAL1, which can anneal RPA-coated single DNA strands during replication-associated DNA damage repair. We used unique genetic tools in Drosophila melanogaster to test whether the fly ortholog of SMARCAL1, Marcal1, mediates annealing during SDSA. Repair that requires annealing is significantly reduced in Marcal1 null mutants in both synthesisdependent and synthesis-independent (single-strand annealing) assays. Elimination of the ATP-binding activity of Marcal1 also reduced annealing-dependent repair, suggesting that the annealing activity requires translocation along DNA. Unlike the null mutant, however, the ATP-binding defect mutant showed reduced end joining, shedding light on the interaction between SDSA and end-joining pathways.

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“…SMARCAL1 depletion also sensitizes cells to similar genotoxic agents including HU, MMC, and camptothecin, but SMARCAL1-deficient cells do not have an increased frequency of SCEs (2,(17)(18)(19). Inherited mutations in SMARCAL1 cause Schimke immunoosseous dysplasia (SIOD), a disease characterized by renal failure, growth defects, immune deficiencies, and a predisposition to cancer (20)(21)(22).Biochemical studies suggest these enzymes do have some degree of specificity dictated by both intrinsic differences in substrate recognition and differences in protein interaction partners and regulation. SMARCAL1, ZRANB3, and HLTF all have an SNF2-type ATPase domain but differ in the accessory domains needed for DNA binding and activity.…”

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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SMARCAL1 deficiency predisposes to non‐Hodgkin lymphoma and hypersensitivity to genotoxic agents in vivo

Cited by 35 publications

References 36 publications

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

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

Annealing of Complementary DNA Sequences During Double-Strand Break Repair inDrosophilaIs Mediated by the Ortholog of SMARCAL1

SMARCAL1 maintains telomere integrity during DNA replication

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