BLM helicase unwinds lagging strand substrates to assemble the ALT telomere damage response.

Autor:	Jiang H; Department of Cancer Biology, Penn Center for Genome Integrity, Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, USA., Zhang T; Department of Cancer Biology, Penn Center for Genome Integrity, Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, USA., Kaur H; Department of Biochemistry and Structural Biology and Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA., Shi T; Department of Cancer Biology, Penn Center for Genome Integrity, Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, USA., Krishnan A; Department of Cancer Biology, Penn Center for Genome Integrity, Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, USA., Kwon Y; Department of Biochemistry and Structural Biology and Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA., Sung P; Department of Biochemistry and Structural Biology and Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA., Greenberg RA; Department of Cancer Biology, Penn Center for Genome Integrity, Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, USA. Electronic address: rogergr@pennmedicine.upenn.edu.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2024 May 02; Vol. 84 (9), pp. 1684-1698.e9. Date of Electronic Publication: 2024 Apr 08.
DOI:	10.1016/j.molcel.2024.03.011
Abstrakt:	The Bloom syndrome (BLM) helicase is critical for alternative lengthening of telomeres (ALT), a homology-directed repair (HDR)-mediated telomere maintenance mechanism that is prevalent in cancers of mesenchymal origin. The DNA substrates that BLM engages to direct telomere recombination during ALT remain unknown. Here, we determine that BLM helicase acts on lagging strand telomere intermediates that occur specifically in ALT-positive cells to assemble a replication-associated DNA damage response. Loss of ATRX was permissive for BLM localization to ALT telomeres in S and G2, commensurate with the appearance of telomere C-strand-specific single-stranded DNA (ssDNA). DNA2 nuclease deficiency increased 5'-flap formation in a BLM-dependent manner, while telomere C-strand, but not G-strand, nicks promoted ALT. These findings define the seminal events in the ALT DNA damage response, linking aberrant telomeric lagging strand DNA replication with a BLM-directed HDR mechanism that sustains telomere length in a subset of human cancers. Competing Interests: Declaration of interests R.A.G. is a co-founder and scientific advisory board member of RADD Pharmaceuticals and a scientific advisory board member for Dong-A ST Co. Neither engagement directly relates to the substance of this study. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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