• 생명과학회지
• /
• 제15권4호
• /
• pp.542-547
• /
• 2005

시스플래틴이나 마이토마이신 C (MMC)와 같은 DNA 사슬간 교차결합 (interstrand cross-link ; ICL) 물질에 대해 Brca1 결손세포들이 보이는 높은 감수성은 Brca1 단백질이 세포의 ICL복구반응에 중요한 역할을 담당하고 있음을 암시하고 있다. Brca1 단백질은 재조합 의존성 또는 재조합 비의존성 경로를 통한 DNA 이중사슬 절단(double-strand break ; DSB) 복구에 필수적인 역할을 담당한다. 최근 본인이 속한 연구그룹에서 재조합 의존성 경로를 통한 세포의 ICL복구반응에 Brca1이 관여한다는 것을 밝혀 보고한바 있다. 본 연구에서는 Brca1 단백질의 재조합 비의존성 복구반응에 대한 관여여부를 $p53^{-/-}$와 $p53^{-/-}\;Brcal^{-/-}$ 세포주를 사용하여 연구하였다. 교차결합 복구 실험에서 Brca1 결손 세포주는 Brca1 정상 세포주보다 현저히 낮은 활성을 보였다. 또한, Brca1 결손세포 주의 MMC 에 대한 감수성과 ICL복구능이 Brca1 단백질 발현을 통해 회복되는 것을 확인하였다. 흥미롭게도, Brca1의 11번 엑손 결손세포주 $(Brca1^{\Delta11})$는 높은 MMC저항성과 ICL 복구능을 보였다. 이러한 결과들을 종합하여 볼 때, Brca1 단백질은 ICL복구에 재조합 의존성 경로뿐만 아니라 재조합 비의존성 경로를 통해서도 관여하며, 이러한 활성에는 엑손 11 부분이 아닌 N 말단의 RING 핑거 도메인이나 C 말단의 BRCT도메인이 중요하다는 것을 알 수 있다.

• Molecules and Cells
• /
• 제45권11호
• /
• pp.792-805
• /
• 2022

Repairing damaged DNA and removing all physical connections between sister chromosomes is important to ensure proper chromosomal segregation by contributing to chromosomal stability. Here, we show that the depletion of non-SMC condensin I complex subunit H (NCAPH) exacerbates chromosome segregation errors and cytokinesis failure owing to sister-chromatid intertwinement, which is distinct from the ultra-fine DNA bridges induced by DNA inter-strand crosslinks (DNA-ICLs). Importantly, we identified an interaction between NCAPH and GEN1 in the chromatin involving binding at the N-terminus of NCAPH. DNA-ICL activation, using ICL-inducing agents, increased the expression and interaction between NCAPH and GEN1 in the soluble nuclear and chromatin, indicating that the NCAPH-GEN1 interaction participates in repairing DNA damage. Moreover, NCAPH stabilizes GEN1 within chromatin at the G2/M-phase and is associated with DNA-ICL-induced damage repair. Therefore, NCAPH resolves DNA-ICL-induced ultra-fine DNA bridges by stabilizing GEN1 and ensures proper chromosome separation and chromosome structural stability.

• Molecules and Cells
• /
• 제38권8호
• /
• pp.669-676
• /
• 2015

Genome instability, primarily caused by faulty DNA repair mechanisms, drives tumorigenesis. Therapeutic interventions that exploit deregulated DNA repair in cancer have made considerable progress by targeting tumor-specific alterations of DNA repair factors, which either induces synthetic lethality or augments the efficacy of conventional chemotherapy and radiotherapy. The study of Fanconianemia (FA), a rare inherited blood disorder and cancer predisposition syndrome, has been instrumental in understanding the extent to which DNA repair defects contribute to tumorigenesis. The FA pathway functions to resolve blocked replication forks in response to DNA interstrand cross-links (ICLs), and accumulating knowledge of its activation by the ubiquitin-mediated signaling pathway has provided promising therapeutic opportunities for cancer treatment. Here, we discuss recent advances in our understanding of FA pathway regulation and its potential application for designing tailored therapeutics that take advantage of deregulated DNA ICL repair in cancer.

• Molecules and Cells
• /
• 제37권8호
• /
• pp.569-574
• /
• 2014

As a scaffold, SLX4/FANCP interacts with multiple proteins involved in genome integrity. Although not having recognizable catalytic domains, SLX4 participates in diverse genome maintenance pathways by delivering nucleases where they are needed, and promoting their cooperative execution to prevent genomic instabilities. Physiological importance of SLX4 is emphasized by the identification of causative mutations of SLX4 genes in patients diagnosed with Fanconi anemia (FA), a rare recessive genetic disorder characterized by genomic instability and predisposition to cancers. Recent progress in understanding functional roles of SLX4 has greatly expanded our knowledge in the repair of DNA interstrand crosslinks (ICLs), Holliday junction (HJ) resolution, telomere homeostasis and regulation of DNA damage response induced by replication stress. Here, these diverse functions of SLX4 are reviewed in detail.