KLLN-mediated DNA damage-induced apoptosis is associated with regulation of p53 phosphorylation and acetylation in breast cancer cells

Cell Death Discovery
Madhav Sankunny, Charis Eng

Abstract

KLLN is a target of p53 involved in S-phase cell cycle regulation deemed necessary and sufficient for p53-mediated apoptosis. Germline promoter hypermethylation of KLLN is associated with a cancer-predisposition syndrome, Cowden syndrome. KLLN's DNA-binding ability is associated with transcription regulation and maintenance of genomic stability. Here, we report on KLLN's role in DNA damage response (DDR) mediated through apoptosis in breast cells with and without a cancer phenotype. KLLN expression was upregulated after doxorubicin-induced DNA damage and this upregulation can be abrogated using RNAi-mediated gene silencing. Silencing KLLN after doxorubicin treatment effected DDR shown by decreased γ-H2AX foci and expression, and apoptosis assessed by decreased frequency of apoptotic nuclei and decreased expression of definitive markers of apoptosis. Contrary to expectations, there was no change in cell cycle regulation after KLLN silencing. These results were observed in breast cells with wildtype and mutant p53. At early timepoints after doxorubicin treatment, knocking down KLLN resulted in decreased Ser15-phosphorylation of p53 but not Thr68-phosphorylation of CHK2 or the phosphorylation of upstream regulators such as ATM and...Continue Reading

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Citations

Jun 26, 2020·Cell Cycle·Niall BuckleyGerry Melino
Jun 23, 2020·Human Molecular Genetics·Lamis Yehia, Charis Eng
Mar 29, 2020·Cell Death Discovery·Ivano Amelio, Gerry Melino
Dec 15, 2019·International Journal of Molecular Sciences·Consuelo PitolliIvano Amelio
Nov 21, 2020·Biology Direct·Ivana CelardoIvano Amelio
Feb 11, 2021·Cell Death Discovery·Ivano Amelio, Gerry Melino
Aug 24, 2021·Pathology, Research and Practice·S Adeleh RazaviMehdi Hedayati

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Methods Mentioned

BETA
ChIP-seq
RNA-seq
flow cytometry
acetylation
transfection
PCR
confocal microscopy
transfections
Protein Assay

Software Mentioned

ImageJ
Leica Confocal Software
Leica Confocal
NIH

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