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Nucleic Acids Res., Oct 01 2024, gkae842 | https://doi.org/10.1093/nar/gkae842 Haplotype-resolved de novo assembly revealed unique characteristics of alternative lengthening of telomeres in mouse embryonic stem cells

Hyunji Lee^1,2, Hiroyuki Niida³, Sanghyun Sung^1,2,*and Junho Lee^1,2,4,*

¹Department of Biological Sciences, Seoul National University, Gwanak-ro 1, Gwanak-gu, Seoul 08826, Korea

²Institute of Molecular Biology and Genetics, Seoul National University, Seoul 08826, Korea

³Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu city, Shizuoka 431-3192, Japan

⁴Research Institute of Basic Sciences, Seoul National University, Seoul 08826, Korea

^*To whom correspondence should be addressed. : Junho Lee

Correspondence may also be addressed to Sanghyun Sung.

Abstract

Telomeres protect chromosome ends from DNA damage responses, and their dysfunction triggers genomic alterations like chromosome fusion and rearrangement, which can lead to cellular death. Certain cells, including specific cancer cells, adopt alternative lengthening of telomere (ALT) to counteract dysfunctional telomeres and proliferate indefinitely. While telomere instability and ALT activity are likely major sources of genomic alteration, the patterns and consequences of such changes at the nucleotide level in ALT cells remain unexplored. Here we generated haplotype-resolved genome assemblies for type I ALT mouse embryonic stem cells, facilitated by highly accurate or ultra-long reads and Hi-C reads. High-quality genome revealed ALT-specific complex chromosome end structures and various genomic alterations including over 1000 structural variants (SVs). The unique sequence (mTALT) used as a template for type I ALT telomeres showed traces of being recruited into the genome, with mTALT being replicated with remarkably high accuracy. Subtelomeric regions exhibited distinct characteristics: resistance to the accumulation of SVs and small variants. We genotyped SVs at allele resolution, identifying genes (Rgs6, Dpf3 and Tacc2) crucial for maintaining ALT telomere stability. Our genome assembly-based approach elucidated the unique characteristics of ALT genome, offering insights into the genome evolution of cells surviving telomere-derived crisis.

논문정보

형식Research article
게재일2024년 10월 (BRIC 등록일 2024-10-02)
연구진국내(교신)+국외 연구진
분야 생명과학 > 세포생물학

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