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Brennan, L. C.

Publications and source records attributed to Brennan, L. C..

2 recordsLinked to original sources

The meiotic synaptonemal complex is assembled from independently regulated gene programmes

Synaptonemal complex (SC) proteins assemble a highly specialised chromosome structure during meiosis and are considered products of a coordinated germline programme that is silenced in somatic cells. Here, we show that this binary model does not describe the regulation of the eight core mammalian SC genes. Despite assembling into a single molecular complex, SC genes follow distinct regulatory trajectories from meiotic entry through SC disassembly. Their activation is staggered, transcripts and proteins persist with different kinetics after SC disassembly begins in late pachytene, and RNA abundance generally fails to predict protein abundance, revealing extensive regulation between transcription and protein accumulation. Integrating promoter state, nascent transcription, RNA and translational measurements identified gene-specific regulatory strategies rather than a shared SC regulatory mechanism. This independence extends beyond the germline and explains how cancers can express individual SC genes. In cancer cells, individual SC loci occupy distinct transcriptional states, including conventional promoter activation, alternative promoter usage, cell-cycle-dependent transcription and promoter competence without detectable productive transcription. DNA methylation can repress individual SC promoters but does not define a common somatic OFF state, while related transcriptional inputs produce different downstream RNA outputs between SC genes. Unexpectedly, single-cell transcriptomes across healthy mouse and human tissues reveal that somatic SC expression is not restricted to cancer: individual SC genes show reproducible associations with specific cell populations, including fibroblasts, myeloid cells, Schwann cells and progenitors. Thus, SC proteins are neither expressed nor silenced as an obligately coupled gene set. We propose that SC identity emerges from the temporally restricted convergence and assembly of independently regulated genes and proteins during meiosis, while their regulatory autonomy permits individual components to be retained or redeployed in normal somatic cells and cancer. The SC therefore represents an emergent molecular state: its components retain distinct regulatory identities, while their transient convergence during meiotic prophase generates a structure and function that none defines individually.

cell biology↗

Moonlighting Role of Meiotic SYCP1 in Breast Cancer: A Chromatin-Bound Regulator of DNA Repair, Transcription, and Drug Resistance

Maintenance of genome integrity is essential for cellular homeostasis, and its perturbation leads to tumorigenesis. Here, we uncover an unanticipated somatic role for the synaptonemal complex protein SYCP1--previously regarded as strictly meiosis-specific--in a broad spectrum of human cancers including breast cancer. Through integrative genomic, proteomic, and functional analyses, we demonstrate that SYCP1 is aberrantly re-expressed in tumor cells, where it actively promotes DNA damage repair, cell cycle progression, and malignant growth. SYCP1 binds chromatin at regulatory elements and directly controls transcriptional programs governing genome maintenance, including key effectors such as CCNB1, PCNA, RAD51C, and H2AX. Loss of SYCP1 impairs DNA repair kinetics, attenuates tumor cell proliferation and migration, and increases sensitivity to chemotherapeutics cisplatin and gemcitabine. Mechanistically, SYCP1 interfaces with chromatin remodeling complexes and transcription factors SP1 and SP2, modulating their genomic occupancy and facilitating oncogenic transcriptional outputs. Clinically, high SYCP1 expression stratifies patients with poor prognosis and therapy resistance across multiple cancer types. Our findings illuminate a previously unrecognized moonlighting function of SYCP1 in somatic cancer cells and position it as a critical chromatin-associated regulator of genome stability, with implications for biomarker development and therapeutic targeting.

cancer biology↗