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Suppression of chromosome healing and anticheckpoint pathways in yeast postsenescence survivors

Xianning Lai1, Jörg Heierhorst

  • 1St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia.

Genetics
|March 29, 2013
PubMed

Insights

Telomere sequences at DNA breaks promote healing in telomerase-positive yeast. In contrast, telomerase-deficient survivors stabilize these breaks, suppressing healing and anti-checkpoint activity.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Telomere repeat-like sequences at DNA double-strand breaks (DSBs) can inhibit DNA damage signaling.
  • These sequences act as seeds for converting DSBs into new telomeres via mutagenic chromosome healing pathways.
  • The response to these telomeric seeds differs between yeast maintaining telomeres via telomerase and those using alternative lengthening of telomeres (ALT) mechanisms.

Purpose of the Study:

  • To investigate the fundamental differences in the response to DSBs with telomere repeat-like sequences between telomerase-positive and telomerase-deficient (ALT) yeast.
  • To elucidate the mechanisms underlying telomere seed stability in ALT cells.
  • To understand the interplay between chromosome healing, DNA damage checkpoint activity, and telomere maintenance pathways.

Main Methods:

  • Comparative analysis of DNA double-strand break (DSB) response in Saccharomyces cerevisiae.
  • Utilizing telomerase-deficient (est2Δ, tlc1Δ) postsenescence survivor yeast strains representing ALT mechanisms.
  • Assessing telomere elongation, end resection, and DNA damage checkpoint activation (RAD9, RAD53) in response to telomere seeds.

Main Results:

  • Telomere seeds are efficiently elongated by telomerase in telomerase-positive cells.
  • In telomerase-deficient ALT survivors, telomere seeds remain remarkably stable, showing no de novo telomerization or extensive end resection.
  • This hyper-stability in ALT cells is associated with, but not directly caused by, prolonged DNA damage checkpoint activity.
  • Both chromosome healing and anti-checkpoint activity of telomere seeds are suppressed in yeast models of ALT pathways.

Conclusions:

  • The response to telomere repeat-like sequences at DSBs is fundamentally distinct between telomerase-dependent and ALT-dependent telomere maintenance pathways.
  • Telomere seeds exhibit hyper-stability in ALT cells, indicating a suppression of mutagenic chromosome healing.
  • Suppression of both chromosome healing and anti-checkpoint activity by telomere seeds is a characteristic feature of yeast ALT pathways.
Keywords:
ALTEst2Rad53Rad9TLC1

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