Genetic disorders associated with defects in DNA repair

Información del proyecto

Identificador del acuerdo de subvención: BMH4983045

Proyecto cerrado

Fecha de inicio 1 Abril 1998

Fecha de finalización 30 Septiembre 2001

Financiado con arreglo a

• Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998

Coste total

Sin datos

Aportación de la UE

Sin datos

Coordinado por

MRC Cell Mutation Unit
United Kingdom

Objetivo

Objectives:

To understand the molecular defects in the genetic disorders associated with deficiencies in nucleotide excision repair, and to relate them to the clinical features of the disorders.
To generate mouse models for these disorders and develop gene therapy strategies.
To understand the molecular basis of disorders associated with defective responses to ionising radiation, and to identify new disorders with such defects.

Approximately ten genetic disorders are now known to be associated with defects in DNA repair or in other cellular responses to DNA damage. Most, but not all, of them are highly cancer-prone, multi system disorders. The aim of this proposal is to understand the molecular and cellular basis of these disorders and to relate them to the clinical features. This will not only provide methods for improved diagnosis, prevention and cures for the disorders, but will also provide insights into more general aspects of differentiation, development and carcinogenesis. The UV-sensitive disorders, xeroderma pigmentosum (XP), Cockayne Syndrome (CS), and trichothiodystrophy (TTD) are all associated with defects innucleotide excision repair (NER) of DNA damage. The gene products defective in TTD, as well as in some XP and CS patients have recently been shown to be subunits of transcription factor TFIIH and to have a dual role in DNA repair and transcription. A major effort will be made to determine why mutations in NER genes sometimes result in cancer-prone but developmentally normal XP, whereas others cause cancer-free, but developmentally abnormal CS and TTD.

These analyses will involve detecting the mutations in different individuals by DNA sequence analysis, determination of the biochemical functions of the encoded proteins in DNA repair and transcription and their interactions, and generation of mouse models containing different mutations, in order to gain insight into disease progression and pathology.

Ataxia-telangiectasia (A-T) is a multi-system cancer-prone disorder associated with sensitivity to ionising radiation. The precise cellular and enzymatic defect has not yet been identified, but the ATM gene has been cloned recently. The ATM protein is a member of an important protein kinase family with domains conserved in Pl 3-kinases. This family of proteins is involved in several different cellular control processes. The role and function of the ATM protein will be studied by purification from cells, determination of its activities and kinase substrates and interacting proteins. The ATM protein is related to the catalytic subunit of DNA-dependent protein kinase (DNA-PK), which has been shown recently to be involved in the repair of DNA double strand-breaks. DNA-PKis defective in the scid mouse, but as yet no human disorder associated with defects in DNA-PK has been identified.

It is likely however that such a defect will be found in individuals with severe combined immunodeficiency, or among subjects who show unusual reactions to radiotherapy. These individuals will be analysed for cellular radiosensitivity, defects in repair of double-strand breaks, defects in DNA-PK and mutations in the ATM gene. This proposal is a development and extension of the Biomed-1 Concerted Action on DNA repair and Cancer, participants in which were responsible for many of the exciting advances in this area over the last few years.

Keywords: Ataxia-telangiectasia, Cell cycle checkpoints, Cockayne Syndrome, DNA repair, radiosensitivity, transcription, trichothiodystrophy, xerodermapigmentosum.

Ámbito científico (EuroSciVoc)

• ciencias médicas y de la salud › biotecnología médica › ingeniería genética › terapia génica
• ciencias naturales › ciencias biológicas › genética › ADN
• ciencias naturales › ciencias biológicas › bioquímica › biomoléculas › proteínas
• ciencias médicas y de la salud › medicina clínica › oncología
• ciencias médicas y de la salud › medicina básica › patología

Programa(s)

• FP4-BIOMED 2 - Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998

Tema(s)

• 4.6 - RARE DISEASES

Convocatoria de propuestas

Datos no disponibles

Régimen de financiación

CON - Coordination of research actions

Coordinador

MRC Cell Mutation Unit

• Aportación de la UE: Sin datos
• Dirección: University of Sussex Falmer ; BN1 9RR Brighton ; Reino Unido
• Coste total: Sin datos