Biology subjects

Bustos, M. R.

Publications and source records attributed to Bustos, M. R..

2 recordsLinked to original sources

bioRxiv2025

MITF maintains genome stability in non-melanocytic cell lineages and suppresses Hippo pathway signaling

Microphthalmia-associated transcription factor (MITF) is crucial for development and survival of melanocytes and serves as a lineage-specific oncogene that is amplified in 10-20% of melanomas. The role of MITF in pathways maintaining genome integrity, such as DNA replication, DNA repair and mitosis has been extensively studied in melanocytes. In addition to its pro-survival role in melanoma, recent studies have shown that MITF expression has important implications for cancer progression and treatment in other cancer types. Nevertheless, studies on the role of MITF in other tissues are scarce. Here, we show that depletion of MITF causes genome instability in non-melanocytic cell lineages, which results in activation of P53, cell cycle arrest and apoptosis. Moreover, we show that P53 activation in MITF depleted cells is dependent on LATS2, a key kinase in the Hippo pathway. Finally, we show that this LATS2 mediated upregulation of P53 is ATR dependent. Collectively, this study highlights the role of MITF as a genome maintenance factor beyond the melanocyte lineage, which might contribute to the tumor suppressive function of MITF.

molecular biology↗

bioRxiv2025

A recurrent pathogenic BRCA2 truncating variant reveals a role for BRCA2-PCAF complex in modulating NF-κB-driven transcription

Germline monoallelic truncating mutations in BRCA2, a critical mediator of homologous recombination (HR), predispose individuals to breast and ovarian cancer. While tumorigenesis is usually attributed to biallelic inactivation, emerging evidence suggests that haploinsufficiency may suffice in certain contexts. To investigate this, we recreated two BRCA2 pathogenic truncating variants in heterozygosis in non-tumorigenic breast epithelial cells. Cells carrying a truncating mutation that was not produced prompted sensitivity to PARP inhibitors (PARPi) and reduced the HR capacity indicating haploinsufficiency. Surprisingly, the other variant was expressed as a truncated product and prompted a transcriptional rewiring. Mechanistically, the truncated BRCA2 product formed abnormal oligomers with full-length BRCA2 and bound to the PCAF acetyltransferase, sequestering it. This led to reduced global histone H4 acetylation and decreased NF-{kappa}B transcriptional activity, ultimately impairing epithelial cell migration--a process also altered in tumors. Our findings uncover a previously unrecognized BRCA2-PCAF axis that modulates NF-{kappa}B-driven transcriptional program, a process that is co-opted by a recurrent BRCA2 pathogenic variant.

cancer biology↗