DNA Repair Disorders

178 Arch Dis Child 1998;78:178–184 REGULAR REVIEW Arch Dis Child: first published as 10.1136/adc.78.2.178 on 1 February 1998. Downloaded from DNA repair disorders C GeoVrey Woods Over the past 30 years a number of rare DNA Exogenous DNA mutants have been classi- repair disorder phenotypes have been deline- cally divided into ultraviolet irradiation, ionis- ated, for example Bloom’s syndrome, ataxia ing irradiation, and alkylating agents. telangiectasia, and Fanconi’s anaemia. In each Ultraviolet irradiation and alkylating agents phenotype it was hypothesised that the under- can cause a number of specific base changes, as lying defect was an inability to repair a particu- well as cross linking bases together. Ionising lar type of DNA damage. For some of these irradiation is thought to generate the majority disorders this hypothesis was supported by of its mutational load by free radical produc- cytogenetics studies using DNA damaging tion. A wide variety of other DNA damaging agents, these tests defined the so-called chro- agents, both natural and man made, are mosome breakage syndromes. A number of the known, many are used as chemotherapeutic aetiological genes have recently been cloned, agents. confirming that some DNA repair disorder phenotypes can be caused by more than one DNA repair gene and vice versa. This review deals only with The DNA double helix seems to have evolved the more common DNA repair disorders. so that mutations, even as small as individual Rarer entities, such as Rothmund-Thomson base damage, are easily recognised. Such syndrome and dyskeratosis congenita, are recognition is usually by a change to the physi- excluded. Some useful addresses are given at cal structure of the DNA double helix. A the end of the paper. number of diVerent pathways are involved in DNA repair. Furthermore, these pathways are DNA damage coordinated with other cellular functions, in DNA is continually subjected to both exog- particular gene transcription and the cell cycle. enous and endogenous mutagenesis. Cells have DNA repair pathways can be classified into built up sophisticated mechanisms to minimise four groups: (1) specific base change repair the eVects of this. Mutations in actively mechanisms; (2) excision repair; (3) recombi- http://adc.bmj.com/ transcribed genes are preferentially repaired national repair; and (4) postreplication repair. and all DNA should be repaired before DNA For many individual base mutations, specific replication when a mutation can become glycosylases have evolved to detect and remove “fixed” and be transmitted to daughter cells. the damaged base. DNA polymerase and ligase Endogenous mutagenesis is the inevitable repair the deletion caused by the removed base. consequence of a large complex molecule The excision repair pathway has been inten- present in a metabolically active environment, sively studied and, although complex, is for example depurination (which occurs be- capable of repairing a wide variety of types of on October 2, 2021 by guest. Protected copyright. cause of the reaction of DNA in water), the DNA damage (see fig 1). Many of the proteins eVect of oxygen and free radicals (causing base involved in excision repair have other damage and DNA strand breaks), and errors functions.3 This pathway preferentially repairs caused by DNA replication (causing base mis- actively transcribed genes, because of the tran- matches and deletions). The scale of endog- scription complex TFIIH. TFIIH is involved in enous mutagenesis is considerable. Depurina- initiating transcription but should transcription tion has been estimated to occur at a rate of halt, TFIIH can recruit excision repair pathway 10 000 bases per day per cell.1 Other DNA proteins and when the repair is complete hydrolysis reactions occur at a lesser rate, reconstitute the proteins required to continue approximately 100-fold slower than depurina- transcription. The cell has recombination tion and reactive oxygen species cause more mechanisms and these are used in meiosis, than 70 diVerent chemical alterations to DNA. mitosis, gene rearrangements, for example DNA replication has a very high fidelity, prob- antibody production, and DNA repair. Recom- ably less than one mutation per cell copied.2 bination repair is vital where both DNA strands However, occasional mistakes are made by the have been damaged, or there has been a double Department of Clinical DNA polymerases miscopying bases (despite strand DNA break. This mechanism involves Genetics, Ashley Wing, proof reading abilities) and also because the proteins which can detect free DNA strands St James’s University DNA polymerase complex skips areas of DNA (one such protein is DNA dependent protein Hospital, Leeds LS9 in which there is a pre-existing mutation kinase, the cause of autosomal recessive severe 7TF present. Such mutations are detected and combined immune deficiency), and recombine Correspondence to: repaired by specific postreplication repair the DNA strands and recruit the DNA Dr Woods. mechanisms. polymerase/ligase complex, as in stage 1e of DNA repair disorders 179 Arch Dis Child: first published as 10.1136/adc.78.2.178 on 1 February 1998. Downloaded from Figure 1 Excision repair is involved in repair of the majority of DNA mutations. Mutations in the XPA-G genes cause the various types of xeroderma pigmentosa, ERCC1 is a protein whose mutated gene causes the excision repair cross complementation group 1 cell line, RPA is replication protein A which binds to single stranded DNA and DNA polymerase synthesise a new DNA strand complimentary to the template strand and DNA ligase links two deoxyribose sugars together with a phosphate group. (A) A site of a mutation in DNA is detected either by the DNA transcription complex “stalling” or by XPA and XPE detecting a conformational change in the DNA double helix. (B) The protein ERCC1 binds to XPA/XPE and recruits XPF which introduces a upstream (5') nick into the mutation bearing DNA strand (arrow). (C)XPB and XPD unwind the 5' end of the mutation bearing single stranded DNA. XPC and XPG introduces a downstream (3') nick into the mutation bearing DNA strand (arrow). (D) XPB and XPD unwind the 3' end of the mutation bearing single stranded DNA, allowing it to detach from its sister chromosome strand. RPA and other proteins stabilise and protect the resultant single stranded gap in DNA. (E) DNA polymerase E/D and other proteins repair the gap using the non-mutated sister DNA strand as a template. (F) DNA ligase links two ribose units together with a phosphate bond. (G) Methylation, other base modifciation, and tertiary structural changes then occur to yield repaired and functional double stranded DNA. http://adc.bmj.com/ excision repair. Postreplication repair occurs spectrum mirrors that seen in the normal immediately after DNA polymerase has pro- population with leukaemia developing at an duced a daughter strand. Before the newly syn- average age of 22 years and other solid thesised daughter strand is methylated, any tumours, particularly of the breast and gas- DNA mutations are detected and repaired. trointestinal tract, by 35 years.7 Germ line mutations in genes in this pathway While the diagnosis of Bloom’s syndrome cause the adult onset autosomal dominant pre- can be suspected clinically, the condition is disposition to bowel cancer, known as heredi- probably not characteristic enough for on October 2, 2021 by guest. Protected copyright. tary non-polyposis colon cancer.4 cytogenetic/molecular genetic confirmation to be omitted. The clinical diVerential diagnosis Bloom’s syndrome includes Dubowitz’s syndrome, Russell-Silver This condition was first described by Bloom in syndrome (including maternal chromosome 7 1954.5 In the past two decades, James German uniparental disomy), chromosome anomalies, in New York, has been the major publisher of fetal alcohol syndrome, and Rothmund- clinical and laboratory data. Thomson syndrome. In only Bloom’s syn- The principal clinical features of this condi- drome does cytogenetic analysis show a six to tion are prenatal and postnatal growth retarda- 10-fold increased rate of sister-chromatid tion, a thin triangular face and a telangiectatic exchanges (see fig 3A). The cytogenetic rash in sun exposed areas, particularly on the laboratory test for sister-chromatid exchange is cheeks (see fig 2A). Birth weight is typically simple to perform and reliable. Prenatal <2500 g at term. Postnatal growth retardation diagnosis has rarely been performed. There- results in an average adult height in males of fore, it should be carried out by a centre with approximately 151 cm and, in females, 144 cm. previous experience and with a combination of Because of the growth retardation, children techniques, that is sister-chromatid exchange may be investigated, often extensively, for rate and mutation detection or linked polymor- causes of failure to thrive.6 Fertility is normal in phic markers. females but probably all males are infertile. Bloom’s syndrome is an autosomal recessive Intelligence is normal. The major complication disorder. The condition is extremely rare, of Bloom’s syndrome is a substantially in- anecdotally less than one case per million in the creased incidence of malignancies. The cancer UK population. The exception is the 180 Woods Ashkenazi Jewish population where the inci- pairs of DNA) was delineated. A gene within dence is one in 10 000. The gene causing this region proved to be the cause of Bloom’s Arch Dis Child: first published as 10.1136/adc.78.2.178 on 1 February 1998. Downloaded from Bloom’s syndrome has recently been cloned syndrome, and is a member of the RecQ and is located on chromosome 15q21.3.8 The helicase protein family, which are capable of discovery was made by the exploitation of the unwinding DNA and RNA. Another gene in increased rate of sister-chromatid exchange the same family of proteins is known to cause seen in Bloom’s syndrome.

Load more