Biology subjects

Venkatachalam, A.

Publications and source records attributed to Venkatachalam, A..

4 recordsLinked to original sources

bioRxiv2026

FANCM restrains structural genome evolution and defines a synthetic lethal dependency in BRCA1-deficient breast cancer

BRCA1 deficient cancers experience persistent replication stress and structural genome instability yet retain the capacity for sustained proliferation, implying reliance on compensatory genome-maintenance mechanisms. Here, we establish BRCA1/FANCM synthetic lethality in human BRCA1 deficient breast cancer and exploit temporally controlled FANCM depletion to capture genome evolution over successive cell divisions before declining cellular fitness becomes limiting. We show that FANCM restrains genome wide structural variation in BRCA1 deficient breast cancer cells under endogenous replication stress. FANCM loss amplifies the characteristic BRCA1 associated short tandem duplication (TD) phenotype while permitting larger, including megabase-scale, TDs and diverse rearrangements to emerge. Newly emerged TDs preferentially associate with Pol II occupied regions, and FANCM depletion increases proximity between the replication machinery and elongating RNAPII in BRCA1 mutant breast cancer cells, linking FANCM-mediated genome protection to transcription replication encounters. BRCA1 altered human tumors with low FANCM expression recapitulate key features of this phenotype, while genome/transcriptome integration links newly emerged SVs to configuration dependent local transcriptional changes. Together, these findings establish FANCM as a replication stress safeguard coupling survival to restraint of structural genome evolution.

cancer biology↗

bioRxiv2026

CRTC, not phosphorylated CREB1, drives cAMP-induced transcription across diverse cell types

Specialized cell types layer cell-type-restricted proteins, metabolites, and organelles onto a shared foundation of core cellular processes. How this ubiquitous machinery generates lineage-specific outputs is central to both cell biology and therapeutic development. G-protein-coupled receptors (GPCRs) respond to receptor-restricted ligands to drive cell-type-specific transcription through cAMP-mediated activation of protein kinase A (PKA), which activates the transcription factor CREB1 through two parallel modes: direct phosphorylation at serine 133, and inhibition of salt-inducible kinases (SIK) that restrain the CRTC coactivators. How these modes integrate and contribute to signaling across cell types has remained unresolved, obscured by genetic redundancy and essentiality. Here we combine focused genetic analyses with a cross-lineage transcriptomic survey to dissect these parallel inputs. In Creb1/Atf1/Crem triple-knockout cells, a non-phosphorylatable mutant CREB1S133A fully rescued endogenous target gene activation, while Crtc1/Crtc2/Crtc3 ablation abolished transcription even with intact CREB1 serine 133 phosphorylation. As part of this mechanism, we found the annotated repressor ICER can instead act as a positive regulator, substituting for full-length CREB1 paralogs to drive a feedforward loop. Across melanocytes, hepatocytes, osteocytes, macrophages, and neurons, SIK inhibition recapitulated cAMP-PKA-driven transcription across both shared and cell-type-specific gene expression programs, with neurons a notable exception. These results invert the canonical model, placing CRTC recruitment as the dominant driver of CREB1-mediated transcription across diverse lineages, reframing how cAMP-PKA signaling can be interpreted and therapeutically targeted.

cell biology↗

bioRxiv2024

Lysosomal reduced thiols are essential for mouse embryonic development

While it has been appreciated for decades that lysosomes can import cysteine, its for organismal physiology is unclear. Recently, the MFSD12 transmembrane protein was shown to be necessary to import cysteine into lysosomes (and melanosomes), enabling the study of these processes using genetic tools. Here, we find that mice lacking Mfsd12 die between embryonic days 10.5-12.5, suggesting that MFSD12 is essential for organogenesis. Within lysosomes, it is well known that a significant fraction of the cysteine is converted into cystine (oxidized cysteine), which accumulates and can be released into the cytosol via the CTNS (cystinosin) transporter. However, in contrast to Mfsd12, loss of Ctns results in live animals, indicating that it is not an essential gene. This suggests that the essential function of MFSD12 is not to enable cystine storage for use in the cytosol but rather to supply reduced cysteine to the lysosomal lumen itself. Consistent with this idea, the treatment of breeding heterozygous mice with cysteamine, a lysosome-penetrant thiol, rescued the development of Mfsd12 knockout mice and resulted in live births. Our work implicates lysosomal thiol import as an essential metabolic pathway and provides tools for deciphering its complex genetic and metabolic interactions.

cell biology↗

bioRxiv2020

Characterization of a RAD51C-Silenced High Grade Serous Ovarian Cancer Model During PARP Inhibitor Resistance Development

Acquired PARP inhibitor (PARPi) resistance in BRCA1- or BRCA2-mutant ovarian cancer often results from secondary mutations that restore expression of functional protein. RAD51C is a less commonly studied ovarian cancer susceptibility gene whose promoter is sometimes methylated in the tumor, leading to homologous recombination deficiency and PARPi sensitivity. For this study, the PARPi-sensitive patient-derived xenograft PH039, which lacks demonstrable repair gene mutations but harbors RAD51C promoter methylation, was selected for PARPi resistance by repeated 21-day niraparib treatments in vivo. PH039 acquired PARPi resistance by the third cycle of treatment and demonstrated unimpeded growth during subsequent exposure to either niraparib or rucaparib. Transcriptional profiling throughout the time course of resistance development showed widespread pathway level changes along with a marked increase in RAD51C mRNA, which reflected loss of RAD51C promoter methylation. Analysis of RAD51C methylation in patient tumor samples from the ARIEL2 Part 1 clinical trial of rucaparib monotherapy likewise indicated that loss of RAD51C methylation prior to on-study biopsy was associated with limited response. Interestingly, the PARPi resistant PH039 model remained platinum sensitive. Collectively, these results not only indicate that PARPi treatment pressure can reverse RAD51C methylation and restore RAD51C expression, but also provide an important model for studying the clinical observation that PARPi and platinum sensitivity are sometimes dissociated.

cancer biology↗