Stress, a global phenomenon is a ticking mite that erodes our well-being. Stress spares no one, not even the tiny organelles inside the cells of an organism. Zooming inside the cells of human beings, even our genetic material i.e. the deoxyribose nucleic acid (DNA) breaks down in stress. The DNA literally undergoes breaks in their double helical structure (known either as ‘single-stranded’ or the ‘double-stranded’ break). But, there’s an enzyme that rescues the stressed DNA when they are in breakdown...the ‘PARP1’ enzyme. How does PARP1 effectively carries out its function in DNA damage? Scientists now have an answer.
Researchers based at the Biotechnology Research and Innovation Council-National Institute of Immunology (BRIC-NII) have elucidated the role of PARP1 enzyme in responding to DNA damage as well as metabolic homeostasis. The research is published in the journal Science Advances.
Dr. Sanjeev Das, principal investigator of the study says, “FDA approved PARP1 inhibitors are used for cancer treatment. However, several instances of failure of such treatment have been reported. Our aim was to decipher the diverse functions of PARP1. Despite its well-established role in DNA repair, the broader regulatory aspects of PARP1 functions are poorly understood”.
Poly(ADP-ribose) polymerase 1 (PARP1) is a multi-faceted and abundant nuclear protein exhibiting roles in DNA repair, chromatin structure, and transcription. It is a cellular stress responder and first among the many signaling proteins recruited near the site of both single-stranded and the double-stranded breaks. Several studies from different groups have reported that PARP1 facilitates DNA damage repair by recruiting other ‘DNA damage repair proteins’ such as XRCC1, MREII, RAD51, and histone-modifying enzymes at the damage site. Histone deacetylase 5 (HDAC5) is one of the histone-modifying enzymes that render a gene on or off by removing the acetyl groups from the histone proteins (histone proteins tightly pack DNA into a compact ‘chromatin’ structure). HDAC5 also interact with other proteins to modulate signaling pathways in different cancers. In addition to DNA damage repair, the PARP1 enzyme modulates genetic transcription. However, the dynamic role of PARP1 in regulating DNA damage repair and transactivation functions is poorly understood.
In this study, the researchers show that HDAC5 exclusively determines PARP1 acetylation status thereby preventing chromatin trapping and triggering the recruitment of repair factors. HDAC5 does this by deacetylating the amino acid lysine at the Lys498 position of the protein. Further, HDAC5-mediated decetylation of the protein at Lys521 position trigger transactivation functions of PARP1 inducing metabolic reprogramming under genotoxic stress conditions. This role of HDAC5 in determining the acetylation status of PARP1 enzyme at Lys498 and Lys521 is critical for PARP1-dependent DNA damage response and transactivation response respectively. This renders PARP1 protein as a bona fide substrate of HDAC5 enzyme. The study also establishes PARP1 novel role in metabolic adaptation to promote tumor progression.
The scientists mapped the dynamic role of PARP1 regulation in damage and metabolic responses using biochemical approach and cutting-edge technologies at the BRIC-NII. The researchers have shown that PARP1 through activating transcription factor 4 (ATF4) induces expression of metabolic genes to maintain cellular energetics. Further, they have also unraveled the oncogenic potential of PARP1 using mouse tumor models thus providing key insights into PARP1 regulation and expand its role in tumor development.
“Future studies could explore therapeutic strategies targeting both the enzymatic and transcriptional functions of PARP1 to effectively treat cancers. The metabolic enzymes induced by PARP1 could also be targeted for therapy” says Dr. Das.
Reference:
Tyagi, W., & Das, S. (2024). Temporal regulation of acetylation status determines PARP1 role in DNA damage response and metabolic homeostasis. Science advances, 10(42), eado7720. https://doi.org/10.1126/sciadv.ado7720