Interferon restores replication fork stability and cell viability in BRCA-defective cells via ISG15

DNA replication and repair defects or genotoxic treatments trigger interferon (IFN)-mediated inflammatory responses. However, whether and how IFN signaling in turn impacts the DNA replication process has remained elusive. Here we show that basal levels of the IFN-stimulated gene 15, ISG15, and its conjugation (ISGylation) are essential to protect nascent DNA from degradation. Moreover, IFNβ treatment restores replication fork stability in BRCA1/2-deficient cells, which strictly depends on topoisomerase-1, and rescues lethality of BRCA2-deficient mouse embryonic stem cells. Although IFNβ activates hundreds of genes, these effects are specifically mediated by ISG15 and ISGylation, as their inactivation suppresses the impact of IFNβ on DNA replication. ISG15 depletion significantly reduces cell proliferation rates in human BRCA1-mutated triple-negative, whereas its upregulation results in increased resistance to the chemotherapeutic drug cisplatin in mouse BRCA2-deficient breast cancer cells, respectively. Accordingly, cells carrying BRCA1/2 defects consistently show increased ISG15 levels, which we propose as an in-built mechanism of drug resistance linked to BRCAness

Interferon restores replication fork stability and cell viability in BRCA-defective cells via ISG15

DNA replication and repair defects or genotoxic treatments trigger interferon (IFN)-mediated inflammatory responses. However, whether and how IFN signaling in turn impacts the DNA replication process has remained elusive. Here we show that basal levels of the IFN-stimulated gene 15, ISG15, and its conjugation (ISGylation) are essential to protect nascent DNA from degradation. Moreover, IFNβ treatment restores replication fork stability in BRCA1/2-deficient cells, which strictly depends on topoisomerase-1, and rescues lethality of BRCA2-deficient mouse embryonic stem cells. Although IFNβ activates hundreds of genes, these effects are specifically mediated by ISG15 and ISGylation, as their inactivation suppresses the impact of IFNβ on DNA replication. ISG15 depletion significantly reduces cell proliferation rates in human BRCA1-mutated triple-negative, whereas its upregulation results in increased resistance to the chemotherapeutic drug cisplatin in mouse BRCA2-deficient breast cancer cells, respectively. Accordingly, cells carrying BRCA1/2 defects consistently show increased ISG15 levels, which we propose as an in-built mechanism of drug resistance linked to BRCAness.</p

Exploring role of 5hmC as potential marker of chemoresistance

Chemoresistance remains to be a common and significant hurdle with all chemotherapies. Tumors gain resistance by acquiring additional mutations. Some of the chemoresistance mechanisms are known and can be tackled. However, the majority of chemoresistance mechanisms are unknown. Our recent findings shed light on one such unknown mechanism. We identified a novel role for 5-hydroxymethycytosine (5hmC), an epigenetic mark on the DNA, in maintaining the integrity of stalled replication forks and its impact on genomic stability and chemoresistance

Proceedings of National Conference on Relevance of Engineering and Science for Environment and Society

This conference proceedings contains articles on the various research ideas of the academic community and practitioners presented at the National Conference on Relevance of Engineering and Science for Environment and Society (R{ES}2 2021). R{ES}2 2021 was organized by Shri Pandurang Pratishthan’s, Karmayogi Engineering College, Shelve, Pandharpur, India on July 25th, 2021. Conference Title: National Conference on Relevance of Engineering and Science for Environment and SocietyConference Acronym: R{ES}2 2021Conference Date: 25 July 2021Conference Location: Online (Virtual Mode)Conference Organizers: Shri Pandurang Pratishthan’s, Karmayogi Engineering College, Shelve, Pandharpur, India