Biology subjects

Chaudhuri, A. R.

Publications and source records attributed to Chaudhuri, A. R..

3 recordsLinked to original sources

bioRxiv2023

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 IFN promotes replication fork stability, cell proliferation and survival in BRCA1/2-defective cancer cells and rescues the lethality of BRCA2-deficient mouse embryonic stem cells. Although IFN activates hundreds of genes, these effects are specifically mediated by the ubiquitin-like modifier ISG15 (IFN-stimulated gene 15). Inactivation of ISG15 or of the enzymes promoting its conjugation, referred as ISGylation, completely suppresses the impact of IFN on the replication process. Depletion of ISG15 significantly reduces cell proliferation rates whereas its upregulation results in increased resistance to the chemotherapeutic drug cisplatin in human BRCA1-mutated triple-negative and mouse BRCA2-deficient breast cancer cells, respectively. Accordingly, cells carrying BRCA1/2 defects consistently show increased ISG15 levels, representing a novel, in-built mechanism of drug resistance linked to BRCAness.

cancer biology↗

bioRxiv2022

Factors regulating translation coupled mRNA degradation in yeast

Codon optimality is a major factor governing translation speed and efficiency, mRNA expression, and stability. Presence of optimal codons maintains a steady translation time, while non-optimal codons can lead to slow peptidyl transfer, prolonged translation time and frequent halt. Owing to this, there are co-translational surveillance protein complexes which monitor this process meticulously and can trigger the release of the mRNA transcript after prolonged halt. The surveillance protein complexes are closely associated with various degradation enzymes which can break down these released transcripts. Degradation of the released transcripts will be ensured if they contain amenable regions for enzyme binding and action. Here, we have used sequence data to estimate the relative abundance of non-optimal codons within a transcript. We found that transcripts with high relative abundance of non-optimal codon show reduced stability and half-life compared to transcripts with lower relative abundance of non-optimal codon. We have further integrated the relative abundance of non-optimal codons with internal unstructured segments for the transcripts, to show that the former is responsible for transcript release and the latter provides susceptible platform for endonuclease cleavage, which together is capable of destabilising and reducing the transcripts half-life. Since this is a translational system, sequestration of mRNA into a dense forest of ribosomes is seen to prolong the transcripts half-life even in the presence of destabilising factors.

bioinformatics↗

bioRxiv2021

Loss of Nuclear DNA ligase III Can Revert PARP Inhibitor Resistance in BRCA1-deficient Cells by Increasing DNA Replication Stress

Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, preclinical and clinical research with PARPi has revealed multiple resistance mechanisms, highlighting the need for identification of novel functional biomarkers and combination treatment strategies. Functional genetic screens performed in cells and organoids that acquired resistance to PARPi by loss of 53BP1 identified loss of LIG3 as an enhancer of PARPi toxicity in BRCA1-deficient cells. Enhancement of PARPi toxicity by LIG3 depletion is dependent on BRCA1 deficiency but independent of the loss of 53BP1 pathway. Mechanistically, we show that LIG3 loss promotes formation of MRE11-mediated post-replicative ssDNA gaps in BRCA1-deficient and BRCA1/53BP1 double-deficient cells exposed to PARPi, leading to an accumulation of chromosomal abnormalities. LIG3 depletion also enhances efficacy of PARPi against BRCA1-deficient mammary tumors in mice, suggesting LIG3 as a potential therapeutic target.

cancer biology↗