PT - JOURNAL ARTICLE AU - Sweta Sikder AU - Sujata Kumari AU - Pallabi Mustafi AU - Nisha Ramdas AU - Swatishree Padhi AU - Arka Saha AU - Birendranath Banerjee AU - Ravi Manjithaya AU - Tapas K. Kundu TI - Non-histone human chromatin protein, PC4 is critical for genomic integrity and negatively regulates autophagy AID - 10.1101/266932 DP - 2018 Jan 01 TA - bioRxiv PG - 266932 4099 - http://biorxiv.org/content/early/2018/02/18/266932.short 4100 - http://biorxiv.org/content/early/2018/02/18/266932.full AB - Multifunctional human transcriptional positive co-activator 4 (PC4) is a bonafide non-histone component of the chromatin and plays a pivotal role in the process of chromatin compaction and functional genome organization. Knockdown of PC4 expression leads to a drastic 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. 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 survivability PC4 knockdown cells. 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 absence of PC4. These data connect the unexplored role of chromatin architecture in regulating autophagy during a stress condition such as radiation.We acknowledge JNCASR, Department of Biotechnology, Government of India for the financial support. TKK is a recipient of Sir J.C. Bose National Fellowship. SS is a CSIR Senior Research Fellow. Part of this work was supported by Wellcome Trust/DBT India Alliance Intermediate Fellowship (500159-Z-09-Z) and JNCASR intramural funds to RM.List of abbreviations and acronymsULK1Unc-51 Like Autophagy Activating Kinase 1ULK2Unc-51 Like Autophagy Activating Kinase 2AMPKα15’AMP-activated protein kinase catalytic subunit alpha-1AMPKα25’AMP-activated protein kinase catalytic subunit alpha-2BECN1Beclin1DRAM1DNA Damage Regulated Autophagy Modulator 1PTENPhosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphataseBCL2Apoptosis regulator Bcl-23-MA3 Methyl adenineshRNAShort hairpin RNABafBafilomycin A1GABARAPL1Gamma-aminobutyric acid receptor-associated protein-like 1GABARAPL2Gamma-aminobutyric acid receptor-associated protein-like 2MAP1LC3B/LC3Microtubule-associated protein 1B light chain 3BMAP1LC3AMicrotubule-associated protein 1A light chain 3A