Open AccessDistinct cellular responses to replication stress leading to apoptosis or senescence
Author(s) -
Lukášová Emilie,
Řezáčová Martina,
Bačíková Alena,
Šebejová Ludmila,
Vávrová Jiřina,
Kozubek Stanislav
Publication year - 2019
Publication title -
febs open bio
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.718
H-Index - 31
ISSN - 2211-5463
DOI - 10.1002/2211-5463.12632
Subject(s) - lamin , senescence , genome instability , biology , dna damage , apoptosis , chromatin , microbiology and biotechnology , cell cycle , carcinogenesis , mutation , chromosome instability , cancer research , genetics , cancer , dna , nucleus , chromosome , gene
Replication stress ( RS ) is a major driver of genomic instability and tumorigenesis. Here, we investigated whether RS induced by the nucleotide analog fludarabine and specific kinase inhibitors [e.g. targeting checkpoint kinase 1 (Chk1) or ataxia telangiectasia and Rad3‐related ( ATR )] led to apoptosis or senescence in four cancer cell lines differing in TP 53 mutation status and expression of lamin A/C ( LA /C). RS resulted in uneven chromatin condensation in all cell types, as evidenced by the presence of metaphasic chromosomes with unrepaired DNA damage, as well as detection of less condensed chromatin in the same nucleus, frequent ultrafine anaphase bridges, and micronuclei. We observed that responses to these chromatin changes may be distinct in individual cell types, suggesting that expression of lamin A/C and lamin B1 ( LB 1) may play an important role in the transition of damaged cells to senescence. MCF 7 mammary carcinoma cells harboring wild‐type p53 (WT‐p53) and LA /C responded to RS by transition to senescence with a significant reduction of lamin B receptor and LB1 proteins. In contrast, a lymphoid cancer cell line WSU ‐ NHL (WT‐p53) lacking LA /C and expressing low levels of LB 1 died after several hours, while lines MEC ‐1 and SU ‐ DHL ‐4, both with mutated p53, and SU ‐ DHL ‐4 with mutations in LA /C, died at different rates by apoptosis. Our results show that, in addition to being influenced by p53 mutation status, the response to RS (apoptosis or senescence) may also be influenced by lamin A/C and LB 1 status.