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Crossan Lab @CrossanLab

We investigate the mechanisms that prevent mutagenesis in the germline. 🧪🧬👨‍🔬 @MRC_LMB

Joined April 2018
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Delighted to share our most recent paper explaining why DNA Translesion Synthesis (TLS) is required for fertility. Huge amount of work from @Pranay_Shahh and a great collaboration with @ReikLab at Altos Labs, @HGLeitch and the Garaycoechea Lab @_Hubrecht Institute (link below)
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In embryonic germ cells loss of the TLS pathway results in increased DNA damage, activation of cell cycle arrest, and the induction of apoptosis - leading to an over 99% reduction in embryonic germ cells and ultimately leading to complete sterility of adults.
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Most surprisingly, upon loss of TLS there is a genome-wide failure of DNA demethylation: a critical step in the process of epigenetic reprogramming during germ cell development, as well as a failure to engage the germ cell transcriptional network.
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Very excited to share our latest work nature.com/articles/s41594-0… published in @NatureSMB ! We find that the Fanconi Anemia DNA crosslink repair pathway restricts L1 retrotransposition during mouse development 🐭🧬 🧵 1/n

Fanconi anemia DNA crosslink repair factors protect against LINE-1 retrotransposition during mouse...

Nature Structural & Molecular Biology - Here the authors show that Fanconi anemia repair proteins protect against LINE-1 retrotransposition, particularly during early development when the...

nature.com
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Finally, we show that not only embryonic but also maternal factors are important to suppress L1 retrotransposition at the earliest stages of development 8/n
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In summary, we find that the Fanconi anemia crosslink repair pathway acts as a ‘fail-safe’ to prevent L1 retrotransposition when other canonical restriction mechanisms are absent. 9/9
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Excited for the pre-print of our latest work to go public! In this study, we discovered that DNA damage tolerance is required for mammalian primordial germ cell DNA demethylation and development biorxiv.org/content/10.1101/… Fantastic collaboration with @ReikLab @HGLeitch 1/9

Primordial germ cell DNA demethylation and development require DNA translesion synthesis

Mutations in DNA damage response (DDR) factors are associated with human infertility, which affects up to 15% of the population. It remains unclear if the role of DDR is solely in meiosis. One...

biorxiv.org
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In all, TLS components are dispensable in the somatic lineages but essential in the germline. PGCs lacking TLS factors fail to express germline genes or perform global DNA demethylation showing a developmental block, explaining infertility of TLS-deficient organisms
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We’d like to thank the @HGLeitch lab and @ReikLab for a wonderful collaboration facilitating the exciting discoveries of this study! There is more data than we could highlight here so please do give the pre-print a read! 9/9
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