FANCM: A new weakness in BRCA1-deficient cancer

Farah Ramadan, Sameer Bikram Shah, Ujwal Subedi, Zachary D. Stephens, Annapoorna Venkatachalam, Neelima Yadav, Vickky Pandit, Sadhana Dubey, Sarah Latka, Hugo Villanueva, Scott H. Kaufmann, Arvind Panday,

Posted on: 3 November 2026

Preprint posted on 10 September 2026

In this preprint, the team of Dr. Panday uncover FANCM as a key suppressor of genome rearrangements and a promising synthetic lethal target in BRCA1-deficient cancer.

Selected by Marta San Martin

Categories: cancer biology, molecular biology

Background

BRCA1 is a tumour suppressor protein with a wide range of cellular functions. Notably, its role in homologous recombination during DNA repair is crucial for the maintenance of genetic stability and its absence is associated with ovarian and breast cancer, including triple negative breast cancer (TNBC) [1, 2]. TNBC is an aggressive cancer type defined by the absence of ER, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) expression.

FANCM is a multifunctional DNA repair factor that promotes the resolution of replication-associated stress by protecting stalled DNA replication forks. It thereby maintains genome stability. BRCA1-deficient tumours, including triple-negative breast cancers, display characteristic patterns of genome instability including R-loop accumulation, transcription-replication conflicts and tandem duplications. FANCM has emerged as a synthetic lethal vulnerability in BRCA1-deficient cells [3]. However, how FANCM prevents genome rearrangements in this context remains poorly understood.

In this preprinted study, the team of Dr. Panday generated a time-controlled FANCM depletion system allowing them to investigate the cellular consequences of FANCM loss before the onset of synthetic-lethal cell death. Thanks to this tool, they identified FANCM as a genome-wide suppressor of structural modifications in BRCA1-deficient TNBC cells and uncovered a central role for FANCM in protecting the genome from replication stress and transcription-replication conflicts.

Overall, this study broadens our understanding of FANCM from a factor acting at individual stalled replication forks to a broader guardian of genome stability and structural genome evolution,, while further highlighting FANCM as a promising synthetic lethal vulnerability in breast cancer.

Key Findings

FANCM is preferentially engaged at replication forks in genomically unstable BRCA1-deficient breast cancer

Firstly, the authors found that BRCA1-mutant tumours exhibited higher levels of both genomic instability and FANCM expression compared to BRCA1-wild-type tumours. They also localized FANCM particles to nascent replication forks in BRCA1-mutant cells indicating that BRCA1-deficient tumours require FANCM for replication fork maintenance.

Temporal analysis of FANCM synthetic lethality reveals structural variant formation in BRCA1-deficient TNBC cells.

The authors next asked whether BRCA1-deficient cells require FANCM for their survival and confirmed this dependency across multiple TNBC cell lines.

Figure 1: Adapted from figure 3A from preprint. To evaluate the effects of FANCM depletion before the onset of synthetic-lethal cell death, the authors took advantage of an inducible shFANCM system. They followed triple-negative breast cancer cell populations for 25 population doublings and analysed the genomic and transcriptomic consequences of FANCM depletion.

One of the most intriguing questions raised in this study was how FANCM loss affects BRCA1-deficient cells over time. However, BRCA1-FANCM synthetic lethality makes this difficult to address. To overcome this problem, the authors elegantly designed a doxycycline-dependent shFANCM system to create a temporal window in which the genomic state of BRCA1-deficient cells could be studied before the onset of synthetic-lethal cell death. This approach not only confirmed FANCM as a synthetic-lethal dependency in BRCA1-deficient cells but also enabled the authors to study its role in maintaining genome integrity.

Genomic and transcriptomic analyses revealed that FANCM depletion leads to more TDs and larger duplications genome-wide, which, interestingly, were associated with transcriptionally active chromatin. Further analysis showed that FANCM loss predominantly generates additional short but also larger duplications, which are distributed across all chromosomes. FANCM depletion also increased transcription-replication conflicts.

Importantly, analysis of human BRCA1-altered breast cancers mirrored these findings, with reduced FANCM expression associated with increased TD signatures and duplication events.

Overall, the data presented in this study suggests that both FANCM and BRCA1 prevent TD formation at different stages of genome maintenance.

Chronic FANCM depletion induces adaptive transcriptional reprogramming in BRCA1-deficient TNBC cells

By analysing gene expression in FANCM-depleted or undepleted TNBC cells, the authors observed that the lack of FANCM leads to a shift in the transcriptional state towards metabolic and stress adaptation programmes. Interestingly, DNA damage response programmes were not dominant. Next, by integrating WGS and RNA-seq data, they found 503 genes located near or within newly emerged structural variants (SVs), yet only a small subset of them were differentially expressed genes. Thus, the transcriptional changes occurring after FANCM depletion are only weakly associated with the newly emerged SVs.

What I like about this preprint

I found the preprint by Ramadan and colleagues particularly interesting, as it builds on a research area closely related to my previous work on BRCA1 interactions and genomic instability.

The authors take an important step beyond examining the synthetic-lethal relationship between FANCM and BRCA1 by studying the consequences of FANCM elimination during the time window between FANCM depletion and the onset of cell death. It is fascinating to see the genomic consequences of FANCM loss and how these findings help explain the interplay between FANCM and BRCA1 in maintaining genome stability.

When FANCM is missing in a BRCA1-deficient setting, there is increased R-loop accumulation, more transcription-replication conflicts and, ultimately, a progressive accumulation of structural variants. I particularly appreciated how the authors were able to connect these different layers, from replication stress and transcription–replication encounters to the emergence of structural genome alterations. The observation that newly arising tandem duplications are preferentially associated with RNA-Pol II regions provides an interesting mechanistic link between transcription and genome instability.

I also found the temporal depletion approach particularly clever, as it allowed the authors to study genome evolution before the loss of cellular fitness. This provides a different perspective on synthetic lethality: rather than only considering FANCM as a dependency required for the survival of BRCA1-deficient cells, the study shows how FANCM actively restrains the ongoing evolution of an already unstable genome.

Overall, I think this study provides an interesting framework connecting synthetic lethality, replication stress and structural genome evolution in BRCA1-deficient breast cancer, highlighting a new potential therapeutic strategy for BRCA1-deficient tumours.

Figure 2: Adapted from figure 10 from preprint. Model for FANCM control of replication. Functional FANCM protects DNA from transcriptional R loops, TRCs and promotes cell survival.

Questions for the authors

Q1: You found interesting differences in gene expression between FANCM-depleted or undepleted BRCA1-mutant TNBC cells. Why do you think DNA damage response pathways were not significantly enriched among the differentially expressed genes?

Q2: Did you expect to find more differentially expressed genes associated with SVs (Figure 9A)? Do you have any mechanistic hypothesis for why this is happening?

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Author's response

Arvind Panday shared

Q1. You found interesting differences in gene expression between FANCM-depleted or undepleted BRCA1-mutant TNBC cells. Why do you think DNA damage response pathways were not significantly enriched among the differentially expressed genes?

This was an interesting aspect of the transcriptional response. Importantly, our RNA-seq analysis was performed after prolonged FANCM depletion, following approximately 25 population doublings, rather than during the acute response immediately after FANCM loss. The cells analyzed therefore represent populations that remained proliferative despite sustained FANCM deficiency and replication stress. Consistent with this, pathway analysis showed suppression of proliferative programs, including MYC targets, E2F targets and the G2M checkpoint, together with enrichment of mitochondrial, metabolic and antioxidant programs.

We therefore interpret the transcriptional profile primarily as a chronic adaptive state of the surviving population, rather than as a transcriptional snapshot of the acute DNA damage response. This distinction is important because FANCM depletion clearly produces genome stress in our experiments: we observe increased R-loops, R-loop-associated replication stress, transcription–replication encounters and γH2AX following FANCM loss. Thus, the absence of dominant DNA damage response pathways in the RNA-seq analysis should not be interpreted as an absence of DNA damage signaling.

One possibility is that canonical DNA damage responses occur earlier following FANCM depletion and are subsequently replaced or accompanied by metabolic and stress-adaptive programs in cells that continue to proliferate under chronic stress. In addition, many proximal DNA damage and replication-stress responses are regulated extensively at the protein and post-translational levels and therefore need not produce a dominant transcriptional signature at the chronic endpoint examined here. Determining the temporal sequence of transcriptional and signaling responses immediately following FANCM depletion will be an interesting direction for future studies.

Q2. Did you expect to find more differentially expressed genes associated with SVs? Do you have any mechanistic hypothesis for why this is happening?

We initially considered that the extensive structural genome evolution accompanying chronic FANCM depletion might account for a substantial fraction of the transcriptional response. However, integration of the longitudinal WGS and RNA-seq data suggested a more nuanced relationship. We identified 503 genes that were intersected by, or located proximal to, newly emerged structural variants, of which 91 were differentially expressed. This indicates that physical proximity to an SV is not by itself sufficient to predict a detectable expression change.

Importantly, when we classified SV–gene relationships according to their structural configuration, specific relationships did show directional transcriptional effects. Genes fully encompassed by deletions were preferentially downregulated compared with SV-unaffected genes (81.8% versus 50.9%; P = 0.037), whereas genes located within 10 kb of BND breakpoints were preferentially upregulated (74.2% versus 49.1%; P = 0.004). Other SV configurations did not show significant directional associations. Thus, the transcriptional consequence of an SV appears to depend not simply on its presence near a gene, but on how that rearrangement is configured relative to the gene.

These observations led us to distinguish two transcriptional consequences of chronic FANCM loss. At the global level, FANCM-deficient cells undergo broad transcriptional adaptation to sustained replication stress, including suppression of proliferative programs and enrichment of metabolic and stress-adaptive pathways. At the local level, a subset of newly emerged SVs is associated with configuration-dependent changes in nearby gene expression.

Mechanistically, we therefore do not favor a model in which the newly emerged SVs are responsible for the majority of the global transcriptional remodeling. Instead, our data suggest that chronic FANCM deficiency produces a broad cellular adaptation to replication stress while structural genome evolution superimposes more localized transcriptional effects at particular rearrangements. An interesting possibility is that these local SV-associated expression changes could, in turn, alter transcriptional activity or replication stress in subsequent cell divisions, creating feedback between structural genome evolution and the cellular stress state. Testing that possibility will require longitudinal analysis linking individual rearrangements to transcriptional changes as they arise.

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