In summary, our work demonstrates that RPA exhaustion can activate SLFN11-dependent cell death in response to replication stress induced from diverse sources and across multiple different cancer cell types. Our work could help explain why SLFN11 is silenced in half of all cancer cell lines. (9/9)

We utilised QIBC to demonstrate that ST1926 potently induces RPA exhaustion, in line with previous work. ST1926 activated ATF4, an ISR-regulated transcription factor, in a SLFN11-dependent manner. Importantly, ATF4 activation was predominantly observed in cells undergoing RPA exhaustion. (8/9)

Finally, we wanted to determine whether RPA exhaustion was a general mechanism to induce SLFN11 activation. By screening various DNA damaging agents and inhibitors of DDR proteins, we found that ST1926, an inhibitor of DNA polymerase alpha, potently induced SLFN11-dependent cell death. (7/9)

Further, we induced RPA exhaustion by performing a titration of siRNA targeting RPA2, which led to a SLFN11- and GCN2-dependent sensitisation of PrimPol KO cells to cisplatin. (6/9)

We hypothesised that RPA exhaustion could activate SLFN11 and promote apoptosis through engagement of SLFN11 with ssDNA. Using an established QIBC technique, we found that PrimPol KO cells exhibited higher rates of RPA exhaustion. (5/9)

We found that the ssDNA binding activity of SLFN11 was required to confer cisplatin sensitivity when repriming was inactivated, which correlated with how PrimPol KO cells were particularly sensitive to loss of the RPA heterotrimeric complex when challenged with cisplatin. (4/9)

Our work discovered that loss of the primase-polymerase PrimPol conferred cisplatin sensitivity only in cell lines that express SLFN11. When repriming is inactivated, cisplatin induces ssDNA accumulation at stalled replication forks, leading to SLFN11- and ISR (GCN2)-dependent apoptosis. (3/9)

SLFN11 is a tRNA nuclease that induces p53-independent apoptosis in response to DNA damage. Half of all annotated cancer cell lines have lost SLFN11 expression, leading to chemoresistance and high tolerance of replication stress. However, how DNA damage activates SLFN11 has remained unclear. (2/9)

We are excited to share that our latest work from the lab aimed at understanding how the tRNA nuclease SLFN11 is activated in response to DNA damage and replication stress has just been published in @natcellbio.nature.com!

Open access link: www.nature.com/articles/s41...

(1/9)

‼️ Excited to share our new paper out now in @science.org ‼️

We describe a new tetrameric RAD51 paralog complex – XRCC3-RAD51C-RAD51D-XRCC2 – which caps the end of RAD51 filaments.

Link: www.science.org/doi/epdf/10....

Thread ⬇️ (1/8)

Distinct ATRX functions cooperate with 9-1-1 and CST complexes to safeguard replication and telomere integrity Mutations in the ATRX chromatin remodeller predispose to a developmental genetic disorder and cancer, but how it safeguards genome and telomere stability remains unresolved. Here, we uncover critical ...

🧬 Preprint alert!

"Distinct ATRX functions cooperate with 9-1-1 and CST complexes to safeguard replication and telomere integrity."

Read the manuscript here 👉 www.biorxiv.org/content/10.1...

New preprint from the lab led by @ssegurabayona.bsky.social identifying SLFN11 activity as a barrier to ALT establishment.

SLFN11 restricts escape from telomere crisis to prevent alternative lengthening of telomeres The tRNA nuclease SLFN11 is epigenetically silenced in ~50% of treatment-naive tumours and is the strongest predictor of chemoresistance but why it is frequently inactivated in cancer is unknown. To a...

🚀 New preprint alert!

We uncover SLFN11 as a molecular gatekeeper that restricts alternative lengthening of telomeres (ALT) by sensing telomere-associated replication stress and triggering apoptosis.

📄 Read the manuscript here: www.biorxiv.org/content/10.1...

Save de date! Join us at @cabimer.bsky.social on October 17th for the @GenomaHubCSIC Workshop in "Genome Dynamics in Development and Disease". Slots available for talks! Registration opens soon!!

Chemical biology: www.linkedin.com/jobs/view/42...
Cell biology: www.linkedin.com/jobs/view/42...
Structural biology: www.linkedin.com/jobs/view/42...

We are looking to recruit three posts at the @crick.ac.uk in structural biology, cell biology, and pharmacology to join a 20+ strong multidisciplinary team focused on delivering the first precision medicines for the treatment of ALT cancers. Interested? Please check out the advertised jobs below:

From the lab to the clinic: developing the next generation of precision cancer therapies Crick group leader Simon Boulton co-founded Artios in 2016, a spin-out from Cancer Research UK’s Commercial Partnerships, where he is now VP of Science Strategy. Artios develops cancer treatments that...

Read our Q&A with Simon Boulton (@boultonlab.bsky.social), a group leader here at the Crick who co-founded the company Artios in 2016.

Artios is a biotech company that develops cancer treatments that target DNA damage response pathways.
www.crick.ac.uk/news-and-fea...

Artios drug exploits ‘replication stress’ in cancer, shrinking subset of tumors in early study Artios Pharma, a startup developing drugs that weaken a tumor’s ability to maintain its DNA, announced positive results in a subset of patients with advanced cancer.

Artios Pharma presented data on its ATR inhibitor (blocks a key DNA damage response enzyme) at #AACR25 today.

50% response (tumor shrinkage) in patients whose tumors lacked a counterpart DNA repair enzyme called ATM.

Read more in my story for @endpts.com

endpts.com/artios-cance...

Artios Pharma Reports Differentiated Clinical Activity in STELLA Phase 1/2a Study for Lead Program ART0380 at the American Association for Cancer Research (AACR) Annual Meeting 2025 - Artios Pharma ART0380 in combination with low-dose irinotecan demonstrated a 50% confirmed overall response rate (cORR) in patients with Ataxia-Telangiectasia Mutated (ATM)-negative1 solid tumors at the recommended...

Exciting results were presented by Artios Pharma at the AACR meeting from their STELLA Phase 1/2a study using their ATR inhibitor ART0380 to target ATM low/negative tumours: www.artios.com/press-releas...