title: SMARCAL1 maintains telomere integrity during DNA replication.
abstract: 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.
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37027;
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Poole
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37027;
authors.forename: Runxiang
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37027;
authors.forename: Gloria G
authors.initials: GG
authors.lastname: Glick
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37027;
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Lovejoy
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37027.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Eischen
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37027; david.cortez@vanderbilt.edu.
authors.forename: David
authors.initials: D
authors.lastname: Cortez
mesh_terms: D000818:Animals; D002877:Chromosomes, Human / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D011995:Recombination, Genetic / Q000502:physiology; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D059505:Telomere Homeostasis / Q000502:physiology*
chemical_list: C412482:SMARCAL1 protein, human; C485869:Smarcal1 protein, mouse; D004265:DNA Helicases; C555409:ZRANB3 protein, human
keywords: SMARCAL1; c-circle; replication stress; telomere