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The role of crosslink repair in primordial germ cells and germ cell tumours

  • Full or part time
  • Application Deadline
    Tuesday, December 03, 2019
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description


Germ cells are uniquely tasked with passing on genetic information. They ultimately give rise to sperm or eggs that come together to produce a new organism with new germ cells. Therefore, the maintenance of genetic integrity in the germline is critical to ensure the faithful transmission of the genome between generations.

Germ cell tumours are the most common malignancy in young men1,2. These tumours are derived from cells in the early embryo or cells of the developing germline1. Both malignant and metastatic germ cell tumours exhibit a characteristic pattern of point mutations (a mutational signature) and recurring gross chromosomal abnormalities – characteristics associated with loss of a particular class of DNA repair prcoess2. Surprisingly, malignant germ cell tumours are extraordinarily responsive to the chemotherapeutic agent cisplatin (a DNA crosslinking agent), with cisplatin resistance predicting a poor survival outcome.

We have recently discovered a unique requirement for a class of DNA repair, known as interstrand crosslink repair, to maintain the genetic stability of germ cells during embryonic development3. The extreme sensitivity of germ cell tumours to DNA crosslinking agents, the nature of the mutational signature of germ cell tumours, and the dependence of embryonic germ cells on crosslink repair suggests that DNA damage caused by crosslinks may drive genome instability in the germ line and contribute to the progression and metastasis of germ cell tumours. This project will build upon these results exploring the relationship between the developmental stage of germ cells and their DNA repair capacity.

Funding Notes

Please see the LMB PhD website for further details: View Website

References


1. Oosterhuis, J.W. & Looijenga, L.H.J. Human germ cell tumours from a developmental perspective. Nat Rev Cancer (2019).
2. Dorssers, L.C.J. et al. Molecular heterogeneity and early metastatic clone selection in testicular germ cell cancer development. Br J Cancer 120, 444-452 (2019).
3. Hill, R.J. & Crossan, G.P. DNA cross-link repair safeguards genomic stability during premeiotic germ cell development. Nat Genet 51, 1283-1294 (2019).


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