1. We are delighted to share our new @cellcellpress on cyclin E-induced whole genome duplication (WGD). This work provides a clue to the mystery as to why many p53-positive tumours have WGD.

Our article "MCM double hexamer loading visualized with human proteins" published in Nature today! ❄️🔬🧬🎉🥳 Great collaboration with John Diffley's lab. Congratulations to Florian Weissmann, Julia Greiwe and all other authors! https://t.co/D13VcIXABT

Spent a fantastic five years @TheCrick doing PhD with @DiffleyLab. John is an amazing mentor and really helped me develop a lot! I will miss everything there in London. Now I have started my postdoc with @doudna_lab in California!

Glad to visit @UoDLifeSciences and meet new friends there. Thanks @YisuiXia for the invitation!

Today in partnership with @GoogleDeepMind we're sharing progress on the next generation of #AlphaFold Our new model greatly expands coverage of structure prediction beyond proteins to other biomolecular classes. Here's how it could advance drug design: https://t.co/ZW8DjYhVDM 🧵

Read this fascinating review on the role of genome doubling in health and cancer from ⁦@GanemLab⁩

A reminder that this closes 30 September!

🎉🎉🎉

Hi all. Two fully funded four year postdoc positions to study DNA replication initiation using human proteins. Please check out the ad and contact me if you want more info. Closing 30 September. https://t.co/YcCRlRTo1l https://t.co/BQTCyG2T1i

Two Drs. in the photo (after I finish my fair number of minor corrections) What a journey! Couldn’t have done it without the amazing mentor @DiffleyLab and friends and family. 🎓🥳 #phd #postviva #NewlyMintedDr

Really happy to see this work out after 4 years of my PhD! A big thanks to John @DiffleyLab and Stephanie Hills who co-led this work with me.

13. We are pleased to see our experimental work correlate with genomics studies in cancer patients, which show that WGD in p53-positive tumours is associated with E2F deregulation, especially amplification of the cyclin E gene.

12. …This is of interest because complete loss of p53 is relatively rare in cancer; some clinically relevant p53 mutants may, therefore, be able to support WGD by both mechanisms

11. We also show that cell lines including those transformed with the viral oncogene SV40 large T antigen have a dampened p53 response and can support WGD driven by DSBs or replicative stress…

10. Davoli and de Lange previously showed that DSBs and telomere attrition induced mitotic bypass and endoreduplication only in p53 deficient cells. We show that replicative stress induces endoreduplication only in p53-proficient cells.

9. Indeed, expression of cyclin E in Aphidicolin-induced RPE1 EC-G1 cells pushes them into S phase. Therefore, cyclin E can 1) induce mitotic bypass and 2) overcome EC-G1 senescence, to allow endoreduplication.

8. Cyclin E-expressing RPE1 cells endoreduplicate and do not enter senescence. We wondered whether it’s because cyclin E can overcome EC-G1 arrest.

7. This is in contrast to DNA damage-induced mitosis bypass, where p53 isn’t required, perhaps due to differential activation of the G2 checkpoint.

6. We show that p21 is the downstream effector of p53 to induce mitotic bypass by inhibiting CDKs. Low CDK activity allows activation of APC/C-Cdh1 to degrade the G2 marker CycB.

5. To our surprise, p53KO cells do not bypass mitosis in replicative stress (RS), but instead enter mitosis that is catastrophic. These cells still have a prolonged G2 checkpoint-dependent arrest, so we reasoned that p53 is specifically required for RS-induced mitotic bypass.

4. Some cell lines can carry on endoreduplication after entering EC-G1 in Aphidicolin whilst hTERT-RPE1 cells, a non-transformed cell line with WT p53, enter a senescence-like state, arresting at EC-G1. We knocked out p53 to see if the RPE1 can endoreduplicate in Aphidicolin.