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조회259

Columbia University

Proc. Natl. Acad. Sci. USA, May 07 2024, 121 (19) | https://doi.org/10.1073/pnas.2318438121 Extrachromosomal telomere DNA derived from excessive strand displacements

Junyeop Lee ^{# 1}, Jina Lee ^{# 1 2}, Eric J Sohn ¹, Angelo Taglialatela ³, Roderick J O'Sullivan ⁴, Alberto Ciccia^{1 3 5}, Jaewon Min^{1 2 5 *}

¹Institute for Cancer Genetics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032.

²Department of Pathology and Cell Biology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032.

³Department of Genetics and Development, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032.

⁴Department of Pharmacology and Chemical Biology, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213.

⁵Herbert Irving Comprehensive Cancer Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032.

^#Contributed equally.
^*Corresponding author: correspondence to Jaewon Min

Abstract

Alternative lengthening of telomeres (ALT) is a telomere maintenance mechanism mediated by break-induced replication, evident in approximately 15% of human cancers. A characteristic feature of ALT cancers is the presence of C-circles, circular single-stranded telomeric DNAs composed of C-rich sequences. Despite the fact that extrachromosomal C-rich single-stranded DNAs (ssDNAs), including C-circles, are unique to ALT cells, their generation process remains undefined. Here, we introduce a method to detect single-stranded telomeric DNA, called 4SET (Strand-Specific Southern-blot for Single-stranded Extrachromosomal Telomeres) assay. Utilizing 4SET, we are able to capture C-rich single-stranded DNAs that are near 200 to 1500 nucleotides in size. Both linear C-rich ssDNAs and C-circles are abundant in the fractions of cytoplasm and nucleoplasm, which supports the idea that linear and circular C-rich ssDNAs are generated concurrently. We also found that C-rich ssDNAs originate during Okazaki fragment processing during lagging strand DNA synthesis. The generation of C-rich ssDNA requires CST-PP (CTC1/STN1/TEN1-PRIMASE-Polymerase alpha) complex-mediated priming of the C-strand DNA synthesis and subsequent excessive strand displacement of the C-rich strand mediated by the DNA Polymerase delta and the BLM helicase. Our work proposes a model for the generation of C-rich ssDNAs and C-circles during ALT-mediated telomere elongation.

논문정보

형식Research article
게재일2024년 05월 (BRIC 등록일 2024-05-03)
연구진국외 연구진
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