Nonhistone human chromatin protein PC4 is critical for genomic integrity and negatively regulates autophagy

• Published in: The FEBS journal 2019-11, Vol.286 (22), p.4422-4442
• Main Authors: Sikder, Sweta, Kumari, Sujata, Mustafi, Pallabi, Ramdas, Nisha, Padhi, Swatishree, Saha, Arka, Bhaduri, Utsa, Banerjee, Birendranath, Manjithaya, Ravi, Kundu, Tapas K.
• Format: Article
• Language: English
• Subjects: AMPK pathway; Architecture; Autophagy; autophagy inhibition; Cell death; Chromatin; chromatin dynamics; Chromosomes; Complementation; Defects; Depletion; Epigenetics; Functional morphology; Gamma irradiation; gamma radiation resistance; Gamma rays; Gene expression; Genomes; histone acetylation; Irradiation; Phagocytosis; Radiation; Radiation tolerance; Transcription
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.14952

Multifunctional human transcriptional positive co‐activator 4 (PC4) is a bona fide nonhistone component of the chromatin and plays a pivotal role in the process of chromatin compaction and functional genome organization. Knockdown of PC4 expression causes a drastic decompaction which leads to open conformation of the chromatin, and thereby altered nuclear architecture, defects in chromosome segregation and changed epigenetic landscape. Interestingly, these defects do not induce cellular death but result in enhanced cellular proliferation, possibly through enhanced autophagic activity. Moreover, PC4 depletion confers significant resistance to gamma irradiation. Exposure to gamma irradiation further induced autophagy in these cells. Inhibition of autophagy by small molecule inhibitors as well as by silencing of a critical autophagy gene drastically reduces the ability of PC4 knockdown cells to survive. On the contrary, complementation with wild‐type PC4 could reverse this phenomenon, confirming the process of autophagy as the key mechanism for radiation resistance in the absence of PC4. These data connect the unexplored role of chromatin architecture in regulating autophagy during stress conditions such as radiation. Non‐histone chromatin protein positive co‐activator 4 (PC4) plays a key role in chromatin compaction and genome organization. Here, Tapas Kundu and colleagues show that PC4 knockdown cells exhibit an open chromatin structure and irregular nuclear shape. Intriguingly, the resulting nuclear defects do not induce cell death but increase cell proliferation via enhanced autophagy. Depletion of PC4 also confers resistance to gamma radiation, through a further increase in autophagy in these cells. These findings highlight the critical role of autophagy, regulated by changes in chromatin architecture, in the cellular response to stress.