DNA repair defects in genetic diseases in man

BIOCHIMIE, 1978, 60, 1173-1:174.

DNA repair defects in genetic diseases in man. D. BOOTSMA.

D e p a r t m e n t o f Cell B i o l o g y a n d G e n e t i c s , Erasmus University, Rotterdam, The Netherlands.

The isolation of r e p a i r deficient m u t a n t s i n microbial systems a n d the genetical a n d biochemical analysis of these m u t a n t s have elucidated a n u m b e r of p a t h w a y s for r e p a i r of DNA damage in p r o k a r y o t i c cells. Comparable approaches for the stu, dy of D NA r e p a i r i n m a m m a l i a n cells have .become available by the use of i n v i t r o cultivated cells. Cultures of skin fibroblaste o b t a i n e d from patients suffering from genetic diseases p r o v i d e d m u t a n t cell strains. Genetic analysis of these mutants was facilitated by the development of somatic cell fusion t e c h n i q u e s [1]. The search for DNA r e p a i r m u t a n t s in m a n was directed to those diseases that showed sensitivity to ultraviolet light (UVL) , a n d X-irradiation, p r e d i s p o s i t i o n to cancer and c h r o m o s o m e i n s t a b i l i t y (<(chromosome breakage s y n d r o m e s >>).

dly sealed in n o r m a l cells, whereas this sealing process seems to be i n h i b i t e d in XP v a r i a n t cells. So far a c o m p l e m e n t a t i o n test has not revealed different c o m p l e m e n t a t i o n groups in this class of XP patients [7].

UVL sensitivity a n d p r e d i s p o s i t i o n to c a n c e r is a p p a r a n t in the genetic skin disease x e r o d e r m a p i g m e n t o s u m (XP) [2]. I n 19~8 Cleaver described a defect i n the r e p a i r of UVL i n d u c e d DNA lesions in c u l t u r e d ceils of XP patients [3]. Eviden.ce is p r e s e n t e d that the XP m u t a t i o n affects an excision r e p a i r process i n v o l v e d i n the removal of UVL i n d u c e d p y r i m i d i n e dimers. By means of cell fusion a c o m p l e m e n t a t i o n test could be performed w h i c h showed that w i t h i n the class of excision deficient XP patients at least 7 different c o m p l e m e n t a t i o n groups can be d i s t i n g u i s h e d [1, 4]. These c o m p l e m e n t a t i o n data suggest the presence of different genes w h i c h most p r o b a b l y are i n v o l v e d i n an early phase of .excision r e p a i r associated w i t h or p r e c e d i n g the e n d o u u c l e o l y t i c step in the p a t h w a y [4, 5]. I n a d d i t i o n to the excision deficient XP a n o t h e r class of XP patients has been identified. Cells of these socalled XP v a r i a n t s p e r f o r m n o r m a l d i m e r excision but are defective in a p o s t r e p l i c a t i o n r e p a i r p a t h w a y [6, 7]. At the molecular level this r e p a i r m e c h a n i s m is not yet fully u n d e r s t o o d [8]. It presents itself as a bypass m e c h a n i s m a l l o w i n g DNA r e p l i c a t i o n to pass DNA lesions p r e s e n t in the p a r e n t a l DNA. Gaps o c c u r r i n g in the daughter s t r a n d s are raptLecture delivered at lhe <,May 31 2, 1.978 on <~Mechanisms of DNA repair >>.

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E v i d e n c e for a DNA r e p a i r defect has been o b t a i n e d i n studies of cell strains from patients w i t h ataxia telangiectasia (AT) (the Louis-Bar s y n d r o m e ) . AT is one of the <> a n d is c h a r a c t e r i z e d by progressive cerebellar ataxia a n d dilatated blood vessels in the eye, p r e d i s p o s i t i o n to c a n c e r a n d sensitivity to X - i r r a d i a t i o n [91. This disease can possibly be c o n s i d e r e d as an e-ray analogue of XP. A r e d u c e d rate of excision of e-ray i n d u c e d DNA base lesions has been observed in cells of a large n u m b e r of AT patients [i0]. Complementation analysis of AT cells has d e m o n s t r a t e d the presence of a least 2 different c o m p l e m e n t a t i o n groups, Although all AT patients studied so far show ,t-ray sensitivity in cell survival experiments only a limited n u m b e r exhibit the excision defect [11]. The m o l e c u l a r nature of the defects in AT has not yet been elucidated. In a n o t h e r <~chromosomes breakage syndrome >>, F a n c o n i ' s a n e m i a (FA), a defect in rep a i r of DNA i n t e r s t r a n d crosslinks and closely spaced o v e r l a p p i n g damage is i n d i c a t e d [12, 13]. This autosomal recessive disease is characterized by growth r e t a r d a t i o n , pigm.entation anomalies of the skin a n d diverses congenital anomalies associated w i t h a progressive insufficiency of the bone m a r r o w . P r e d i s p o s i t i o n to c a n c e r is clearly indicated. FA cells are highly sensitive to the cytotoxic a n d chromosomes breakage action of b i f u n c t i o n a l a l k y l a t i n g agents [12]. Several other genetic diseases are possible candidates for m u t a n t s in DNA r e p a i r i n man. Bloom's s y n d r o m e , the t h i r d of the <~chromosome breakage s y n d r o m e >> has been extensively investigated. So far, no evidence for defective DNA rep a i r has been o b t a i n e d [14]. An i n t e r e s t i n g feature of Bloom's cells is the high s p o n t a n e o u s rate of sister c h r o m a t i d exchanges [15]. This phenom e n o n and the characteristic c h r o n m s o m e insta-

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b i l i t y i n B l o o m c e l l s s u g g e s t t h e p r e s e n c e of a cellular defect in which DNA repair in an unk n , o w n m a n n e r m i g h t b e i n v o l v e d [14]. So f a r i n n e i t h e r of t h e d i s e a s e s s t u d i e d t h e p r i mary gene products affected by the mutations have been identified. However, the introduction of g e n e t i c d i s e a s e s i n t h e s t u d y of D N A r e p a i r m e c h a n i s m s i n h u m a n cells h a s o p e n e d a ne-w f i e l d of r e s e a r c h w h i c h u n d o u b t e d l y w i l l c o n t r i b u t e t o t h e u n d e r s t a n d i n g of D N A r e p a i r a n d its r o l e i n m u t a g e n e s i s a n d c a r c i n o g e n e s i s [16].

R~F~BR,EN,C'ES. I. de Weerd-Kastelein, E. A., Keijzer, W. a Bootsma, D. (1972) Nature New Biol., 238, 80. 2. l~obbins, J. H., Kraemer, K. H., Lutzner, M. A., Festoff, B. W. ,~ Coon, H. G. (197'4) Ann. Intern. Med., 80, 2.~1. 3. Cleaver, J. E. (19'68') Nature, 218, 652. 4. Bootsma, D. (1978) In <> 0W. W. Nichols & D. G. Murphy, eds) Symposia Specialists Inc., Miami, U.S.A., pp. 21-36.

BIOCH1M1E, 1978, 60, n ° 10.

6. L e h m a n n , A. R., Kirk-Bell, S., Arlett, C. F., P a t e r son, M. C., L o h m a n , P. H. M., de Weerd-Kastelein, E. A. ,~ Bootsma, D. (19,75) Proc. Nat. Acad. Sci. USA, 72, 219. 7. L e h m a n n , A. R., Kirk-Bell, S. a Jaspers, N. G. J. (1977) In <> (W. W . Nichols a D. G. Murphy, eds) Symposia Sipeeialists Inc., Miami, U.S.A., pp. 203-215. 8. Cieaver, J. E., W i l l i a m s , J. I., Kapp, L. a Park, S. D. (1978) In <>, ICN-UCLA Symposia on Molecular a n d Cellular Biology, vol. IX (P. C. Hanawalt, E. C. Friedberg a C. F. Fox, eds) Academic Press, New York, N.Y. (19789. In the press. 9. Kraemer, K. H. (19}77) In <> (W. W. Nichols ,¢ D. G. Murphy eds), Symposia Specialists Inc., Miami, U.S.A., pp. 37-71. 10. Paterson, M. C., Smith, B. P., L o h m a n , P. H. M., Anderson, A. K. ~ F i s h m a n , L. (1976) Nature, 260, 444. 1I. Paterson, M. C., Smith, B. P., Kn.ight, P. A. & Anderson, A. K. (I9.77) I n <> (Castellani, A., ed). P l e n u m P u b l i s h i n g Corporation, New York, pp. 207-218. 12. S,asaki, M. S. (1978) In <~, ICN-UCLA Symposia on Molecular a n d Cellular Biology, vol. I~X (P. C. Han,awalt, E. C. Friedberg C. F. Fox, eds) Academic Press, New York, N.Y. (1978). In the press. 15. Chaganti, R. S. K., Schonberg, S. a German, J. 1974) Proc. Nat. Acad. Sci., 71, ~508. 16. Setlow, R. B. (19'78) Nature, 271, 713.