Distinct cellular responses to replication stress leading to apoptosis or senescence

0510201 - BFÚ 2020 RIV GB eng J - Journal Article
Lukášová, Emilie - Řezáčová, M. - Bačíková, Alena - Sebejova, L. - Vávrová, J. - Kozubek, Stanislav
Distinct cellular responses to replication stress leading to apoptosis or senescence.
FEBS Open Bio. Roč. 9, č. 5 (2019), s. 870-890. ISSN 2211-5463. E-ISSN 2211-5463
R&D Projects: GA ČR GBP302/12/G157; GA MZd NV16-29835A
Institutional support: RVO:68081707
Keywords : oncogene-induced senescence * dna-damage response * h2ax phosphorylation * cancer-cells * atr * chk1
OECD category: Biochemistry and molecular biology
Impact factor: 2.231, year: 2019
Method of publishing: Open access
https://febs.onlinelibrary.wiley.com/doi/pdfdirect/10.1002/2211-5463.12632

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 TP53 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 (LB1) may play an important role in the transition of damaged cells to senescence. MCF7 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 LB1 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 LB1 status.
Permanent Link: http://hdl.handle.net/11104/0300726