Quaas Marianne, Kohler Robin, Nöltner Lukas, Schmidbauer Louisa F, Uxa Sigrid, Müller Gerd A, Engeland Kurt
Molecular Oncology, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
Department of Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery, University Hospital Leipzig, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
Cell Death Differ. 2025 Aug 22. doi: 10.1038/s41418-025-01566-9.
BRCA1 and BRCA2 proteins are crucial for DNA repair through homologous recombination (HR), which predominantly takes place during S and G phases. Their expression is tightly regulated to ensure HR occurs exclusively within these phases. While these proteins are well-established tumor suppressors in hereditary breast and ovarian cancers, their inactivation is rare across all sporadic cancers. Counterintuitively, BRCA1 and BRCA2 expression is downregulated rather than upregulated following DNA damage and p53 activation. In this study, we demonstrate that BRCA1 and BRCA2 gene expression is governed by the same transcriptional mechanisms throughout the cell cycle, peaking in the S phase. During G/G and following p53 activation, BRCA1/2 transcription is repressed by DREAM and RB:E2F repressor complexes. Importantly, this transcriptional repression occurs concurrently with the coordinated downregulation of numerous genes involved in cell cycle control and DNA repair pathways. Consistent with previous findings, this suppression notably affects members of the Fanconi anemia group and is mediated through the DREAM complex. Such broad transcriptional suppression facilitates exit from S phase, thereby promoting a fundamental shift in DNA repair mechanisms. Following DNA damage, we demonstrate that BRCA1/2 downregulation occurs indirectly through the p53-p21-DREAM/RB axis, wherein p53-induced p21/CDKN1A expression initiates repression dependent on DREAM and RB. These results, together with observations from previous studies, suggest that DNA repair shifts from HR to the error-prone pathways of non-homologous end joining (NHEJ) and single-strand annealing (SSA), resulting in chromosomal aberrations and cell death, thereby in fact preventing malignant transformation. Our findings elucidate the transcriptional regulation of BRCA1 and BRCA2 expression. These regulatory mechanisms, when considered alongside prior findings and hypotheses, may help explain why BRCA1 and BRCA2 proteins do not exhibit tumor-suppressive functions in most cell types.
BRCA1和BRCA2蛋白对于通过同源重组（HR）进行的DNA修复至关重要，同源重组主要发生在S期和G期。它们的表达受到严格调控，以确保同源重组仅在这些阶段发生。虽然这些蛋白在遗传性乳腺癌和卵巢癌中是公认的肿瘤抑制因子，但在所有散发性癌症中它们的失活情况很少见。与直觉相反，DNA损伤和p53激活后，BRCA1和BRCA2的表达下调而非上调。在本研究中，我们证明BRCA1和BRCA2基因表达在整个细胞周期中受相同的转录机制调控，在S期达到峰值。在G/G期以及p53激活后，BRCA1/2转录受到DREAM和RB:E2F抑制复合物的抑制。重要的是，这种转录抑制与许多参与细胞周期调控和DNA修复途径的基因的协同下调同时发生。与先前的研究结果一致，这种抑制显著影响范可尼贫血组的成员，并通过DREAM复合物介导。如此广泛的转录抑制促进了从S期退出，从而推动了DNA修复机制的根本转变。DNA损伤后，我们证明BRCA1/2下调是通过p53-p21-DREAM/RB轴间接发生的，其中p53诱导的p21/CDKN1A表达启动依赖于DREAM和RB的抑制。这些结果与先前研究的观察结果一起表明，DNA修复从同源重组转变为易错的非同源末端连接（NHEJ）和单链退火（SSA）途径，导致染色体畸变和细胞死亡，从而实际上阻止了恶性转化。我们的研究结果阐明了BRCA1和BRCA2表达的转录调控。这些调控机制，与先前的研究结果和假设一起考虑时，可能有助于解释为什么BRCA1和BRCA2蛋白在大多数细胞类型中不表现出肿瘤抑制功能。
