Characterisation of a novel BRCA1 regulation required for the protection of stalled DNA replication forks

Daza Martin, Manuel (2018). Characterisation of a novel BRCA1 regulation required for the protection of stalled DNA replication forks. University of Birmingham. Ph.D.

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Abstract

Lesions in DNA can lead to accumulation of mutations that may cause cancer progression and disease. DNA repair is essential to overcome these lesions maintaining genomic integrity and preserving the genetic information, following DNA damage a wide variety of post-translational modifications (PTM) take place and phosphorylation is an essential one.

A key DNA repair factor is BRCA1, a tumour suppressor gene that encodes a protein that can form 3 different complexes implicated in several mechanisms of DNA repair, interestingly BRCA1 mutations can lead to an increased risk of having breast and ovarian cancer by the age of 70. An important binding partner of BRCA1 is PALB2 a cancer predisposition gene that is essential for accurate HR repair, however it is yet not well understood whether the BRCA1-PALB2 interaction is involved in other DNA repair mechanisms.

An important role of BRCA1 is to promote replication fork stability by protecting nascent DNA at stalled replication forks from degradation, and this function is essential to preserve genomic integrity but it remains unclear how BRCA1 regulates replication fork stability and fork protection.

In this thesis we suggest that the ability of BRCA1 to protect nascent DNA is regulated in an unexpected fashion through CDK phosphorylation at Serine 114 and PIN1-mediated conformational change. Our data also reveals dual roles of PALB2 and BRCA1 at stalled replication forks, as restart and protection are separate, and interestingly unclassified patient variants within the CDK-PIN1 regulated region of BRCA1 exhibit deleterious fork protection. Altogether findings in this thesis suggest a previously unrecognised regulation pathway where CDK1, 2-BRCA1-PIN1-PALB2 cooperate together to govern fork stability.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):