Molecular mechanisms for adapting to chronic UV exposure

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K07290
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Molecular biology
• Research Institution: Gakushuin University
• Principal Investigator: Hishida Takashi 学習院大学, 理学部, 教授 (60335388)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: DNA損傷 / 出芽酵母 / DNA相同組換え

Outline of Final Research Achievements

UV-induced DNA lesions are a potential source of genome instability, which can increase the risk of cancer and induce premature aging in humans. Here, we examined growth and genome stability in NER-defective haploids (rad14 mutants) during chronic low-dose UV (CLUV) exposure, focusing on adaptive changes in fitness. We found that haploid rad14 mutants became diploid following CLUV, and evolved diploids were more resistant to CLUV than haploids. Strikingly, accumulation of single-stranded DNA gaps, but not UV-induced photoproducts, contributed to diploid cell fitness. Consistently, inter-homologue recombination involved in generating loss of heterozygosity (LOH) was increased in CLUV-exposed rad14 deletion diploids. These results demonstrate that HR plays an essential role in maintaining the proliferating potential in CLUV-exposed rad14 mutants, but results in a frequent outcome of LOH, both of which are a hallmark of cancer.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

遺伝情報物質であるDNAでは、様々なDNA損傷が常に起こっている。そのため、DNA修復機能の欠損はゲノム不安定性の増大を引き起こし、ヒトの発がんリスクを顕著に増加させることが知られている。本実験では、紫外線によるDNA損傷の修復に関与するヌクレオチド除去修復を欠損した酵母細胞を用いて紫外線ストレス耐性機能および染色体構造に及ぼす影響を解析した。その結果、相同染色体間で起こる組換えがストレス耐性機能の向上とゲノム不安定性の増加というトレードオフの関係を生みだしていることが明らかになった。この結果は、DNA相同組換えが発がんの過程で重要な役割を果たしていることを示唆している。