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SUMMARY OF RESEARCH
The human genome contains regions that are rich in repetitive DNA, such as telomeres or centromeres but repetitive sequences are also scattered across the genome with no apparent function and must be accurately replicated, transcribed and repaired when broken.
Important studies have described that repetitive sequences are prone to breakage, disrupt gene transcription or splicing and get expanded or contracted. These events trigger repeat-induced instability and fragility, which is common in neurodegenerative hereditary disorders, collectively known as repeat expansion disorders, including Huntingtons disease, Myotonic dystrophy, and Fragile X syndrome.
Historically, a challenge in the study of repetitive sequences is that genomic screens performed in a disease-specific context could not accurately map novel repeat expansions. However, development of long-read sequencing technologies, including PacBio and Nanopore, together with computational methods, such as GangSTR and Expansion Hunter, have exponentially enhanced the discovery of novel repeat expansions in human disorders. Remarkably, for the first time, short tandem repeats have been identified as expanded in renal and prostate cancer and neuropsychiatric disorders, such as bipolar syndrome and schizophrenia.
However, these studies provide a mere correlation between repeat expansions and disease and lack mechanistic evidence on if and how they might trigger disease onset. The discovery of novel repeat expansions associated with cancer promotes an unprecedented opportunity to study these repeats in an isolated manner to elucidate the following questions: What is the physiological consequence of repeat expansion in non-transformed and transformed cell lines? How does expansion act as a direct source of genomic instability? What factors are required to prevent repeat instability in vitro? What strategies can be employed to develop therapeutic interventions targeting repeat expansions?
My vision it to study repeat expansions recently associated with cancer, and neuropsychiatric disorders, to mechanistically dissect if and how they drive disease progression. My research proposes an innovative and multidisciplinary approach that combines, cell biology and biochemistry, to study repeat expansions in both normal and disease context. In the long term, this work will serve as a strong methodological and conceptual foundation to identify novel repeats as biomarkers associated with disease and the development of strategies for targeted interventions, potentially impacting patient treatment.
These research lines are funded by:
Programa Ramon y Cajal con atracción de talento (February 2024-February 2029): Manuel Daza Martin. Funding body: Ministerio de Ciencia, Innovación y Universidades. Agencia estatal de investigación. Unión Europea.
Ayudas de Atracción de Talento CSIC (November 2023): Manuel Daza Martin. Funding body: CSIC.
La Caixa Postdoctoral Junior Leaders (March 2023): Manuel Daza Martin. Funding body: La Caixa (Gratefully declined).
These research lines are supported by the following publications:
CS. Casas-Delucchi*, M. Daza-Martin*, SL. Williams, G. Coster (AC). (1/4). 2022. "The mechanism of replication stalling and recovery within repetitive DNA". Nat Commun. 19;13(1):3953. DOI:10.1038/s41467-022-31657-x. *Equal contribution.
M. Daza-Martin (AC), RM. Densham (AC), JR. Morris (AC). (1/3). 2019. "BRCA1-BARD1: the importance of being in shape". Mol Cell Oncol.
11;6(6):e1656500. DOI: 10.1080/23723556.2019.1656500.
M. Daza-Martin, K. Starowicz, M. Jamshad, et al. RM. Densham (AC), JR. Morris (AC). (1/17). 2019. "Isomerization of BRCA1-BARD1 promotes replication fork protection". Nature. 2019 Jul;571(7766):521-527. DOI:10.1038/s41586-019-1363-4.
AJ. Garvin, AK. Walker, RM. Densham, AS. Chauhan, HR. Stone, HL. Mackay, M. Jamshad, K. Starowicz, M. Daza-Martin, et al. JR. Morris (AC). (9/13). 2019. "The deSUMOylase SENP2 coordinates homologous recombination and nonhomologous end joining by independent mechanisms". Genes Dev. 1;33(5-6):333-347. DOI: 10.1101/gad.321125.118.
FUNDING AGENCIES LAST 5 YEARS
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