المساعد الشخصي الرقمي

مشاهدة النسخة كاملة : DNA Repair


ملكــة الصــمت
02-22-2007, 10:41 AM
What is DNA Repair?

http://tango01.cit.nih.gov/sig/dna/dnarf1.gif

Figure 1 -DNA Repair functions
As a major defense against environmental damage to cells DNA repair is present in all organisms examined including bacteria, yeast, drosophila, fish, amphibians, rodents and humans. DNA repair is involved in processes that minimize cell killling, mutations, replication errors, persistence of DNA damage and genomic instability. Abnormalities in these processes have been implicated in cancer and aging (Figure 1).

http://tango01.cit.nih.gov/sig/dna/dnarf2.gif

Figure 2 - Mammalian DNA Repair Systems
There are several different repair pathways in mammalian cells (Figure 2):

a) single step reactions, a direct reversal by a single enzyme like photolyase or O-6-methyl-DNA-alkyltransferase,

b) single and multi-step base excision mechanisms (i.e., glycosylases) and

c) multi-step reactions with pleiotropic specificities from multiple protein components.
An example of the single step reaction is the direct reversal that can be accomplished by the bacterial photolyase enzyme: a cyclobutane pyrimidine dimer is converted into two adjacent pyrimidines, and thereby the lesion is repaired.

Another multi-step process is the one seen after mismatch formation, often a consequence of a replicative error. In E. coli, these mismatch bases are repaired by a set of enzymes, the MutS, MutL and MutH proteins. The MutS protein recognizes the lesion, and initiates the assembly of a repair complex containing all three proteins. The MutH protein incises at a GATC sequence in the unmethylated strand. Next, a MutS, MutL and MutU dependent excision step removes a section of DNA containing the GATC site and the mismatch. The resulting single stranded gap is filled in by DNA polymerase III. There is currently much interest in what the homologous pathway is in mammalian cells, and whether there is interaction between it and nucleotide excision.
Simple base modifications such as monofunctional alkylations can be removed by the base excision repair system whereas more complex, bulky lesions are dealt with by the nucleotide excision repair pathways.

Recombinational repair has been well characterized in bacteria, but these processes are not well defined in mammalian cells. When there is no available intact template for the DNA polymerase to copy, a recombination must take place. An example of this type of repair is the process involved in the removal of chemotherapeutically introduced DNA interstrand crosslinks which are typically introduced after treatment with nitrogen mustards or cisplatin.

http://tango01.cit.nih.gov/sig/dna/dnarf3a.gif

Figure 3 - Nucleotide Excision Repair scheme
The most important DNA repair pathway is nucleotide excision repair (figure 3) that fixes the majority of bulky lesions in DNA. These lesions include UV induced photoproducts, and bulky adducts such as those derived from cisplatin and 4-nitroquinoline oxide. Understanding of the enzymology was previously based on knowledge from work done in E.coli, but now the molecular events are being characterized in human cells. Nucleotide excision repair involves recognition, incision, degradation, polymerization, and finally, ligation. The recognition steps involve the ERCC1, XPA and XPF gene products followed by the interaction with the TFIIH transcription factor. This factor contains the repair genes XPB and XPD and thus represents a direct molecular link between DNA repair and transcription. A dual incision event is accomplished by the ERCC1 and XPG products, and this is followed by excinuclease activity, polymerization and ligation. There are a number of recent reviews that discuss this pathway in detail and compare the pathways in bacteria and mammalian cells .

Nucleotide excision repair pathways differ in different parts of the mammalian genome: separate pathways operate for the repair of active or essential genomic regions versus regions that are non coding. The in vitro cell free extract assays, that have been used with considerable success to determine aspects of the DNA repair enzymology, are all limited to studying inactive DNA, and as yet there is no assay for in vitro repair of active genes in mammalian cells. Several laboratories are working on this problem, and that approach is necessary for optimal biochemical analysis of the biochemistry of gene specific DNA repair. There are distinct DNA repair pathways for the bulk genome (inactive genomic regions) and for gene specific repair of active genes. Some genes may have preferential repair and even a strand bias of the repair process, and these need to be understood. Further, there can be variations within genes as well: certain codons are repaired better than others.

A few human disorders are characterized by defects in DNA repair. Patients with xeroderma pigmentosum (XP) have clinical sun sensitivity, extensive freckle-like lesions on sun exposed skin and an approximate 1000-fold increase of developing skin cancer (basal cell carcinoma, squamous cell carcinoma and melanoma). About 20% of the XP patients have progressive neurologic degeneration. XP cells are hypersensitive to UV- induced cell killing and cell mutations and have defective DNA repair. There are 7 XP nucleotide excision repair complementation groups (XP-A to XP-G) plus a variant form with normal excision repair. The genes that are defective in XP are involved in the nucleotide excision repair and basal transcription complexes (see above) (figure 3).
Patients with Cockayne syndrome have sun sensitivity, short stature, and progressive neurologic degeneration. Unlike XP, Cockayne syndrome is not associated with cancer. Cultured cells from Cockayne syndrome patients are hypersensitive to killing by UV and have defective DNA repair of actively transcribing genes. There are 2 complementatoin groups in Cockayne syndrome. The genes that are defective in Cockayne syndrome are also involved in both nucleotide excision repair and transcription however, their precise function is not yet known.

Patients with trichothiodystrophy (TTD) have photosensitivity, short stature, mental retardation and sulphur deficient brittle hair. TTD is not associated with cancer. Cells from TTD patients are hypersensitive to killing by UV and have defective DNA excision repair. The genes that are defective in TTD have been found to be in XP complementation group D or in unique TTD complementation groups. The explanation for the marked differences in clinical features of patients with mutations in the same

ملكــة الصــمت
02-22-2007, 10:44 AM
Some recent references for more information:

Bohr, V.A., Wassermann, K., and Kraemer, K.H. DNA Repair Mechanisms, Alfred Benzon Symposium No. 35, Copenhagen:Munksgaard, 1993.pp. 1-428.

Cleaver, J. and Kraemer, K.H.: Xeroderma pigmentosum and Cockayne syndrome. In Scriver, C.R., Beaudet, A.L., Sly, W.S., and Valle, D. (Eds.) The Metabolic and Molecular Basis of Inherited Disease, Seventh Edition. New York, McGraw Hill, vol III, pp 4393-4419, 1995.
Friedberg, E.C., Walker, G.C., and Siede, W. DNA repair and mutagenesis, Washington, D.C.ASM Press, 1995. pp 1-698.

Science 266: December 23, 1994 DNA Repair - Molecule of the Year. This issue contains a series of review articles on DNA repair. pp1954-1960.
Trends in Biochemical Sciences (TIBS) vol 20 No 10: October 1995 (237). This issue is entirely devoted to review articles on DNA repair. pp. 381-440

نايف
02-22-2007, 11:33 AM
عدتي لابداعاتك اختي ملكه فلك الشكر

ملكــة الصــمت
02-22-2007, 02:14 PM
عدتي لابداعاتك اختي ملكه فلك الشكر

كل الشكر لمرورك اخوي ...

yaak
02-23-2007, 02:38 AM
رائع ملكة الصمت على الموضوع

الحقيقه احس مواضيعي ولا شي عند اللي انتي كاتبته :sad:

بس حبيت اشارك بهالصوره المتواضعه احس انها راح تخدم الموضوع

http://www.llnl.gov/bio/groups/dna_repair/images/Intro_oxid_damage.jpg


شكرا لكِ :rabbi:

ملكــة الصــمت
02-23-2007, 02:45 AM
مرحبا ياك

ايش التواضع دا:biggrin:

الف شكر لتواجدك وللصورة الرائعة ... اضافة مميزة:friends:

yaak
02-23-2007, 03:05 AM
مو مسأله تواضع يا ملكة .... بس هذي الحقيقه

شكرا اختي :telephone:

ملكــة الصــمت
02-23-2007, 03:06 AM
شكرا لمروك الطيب :friends:

خالــد
02-23-2007, 04:08 PM
ماشاء الله ملكة

دائما متألقة

الى المفضلة

و شكرا لك

ملكــة الصــمت
02-23-2007, 09:59 PM
ماشاء الله ملكة

دائما متألقة

الى المفضلة

و شكرا لك

العفو أخوي

أهلا برجوعك نور المنتدى ...

نجــم
02-23-2007, 10:10 PM
ملكة الصمت
قولي يالله ..

قولي يا الله

يا الله
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انه يوفقك ويعطيك العافية ..
اللهم لا حسد .. ما لقيت شي ينضااف للمقال :biggrin:

دام حضورك .. دام فرحك

ملكــة الصــمت
02-24-2007, 02:34 AM
ملكة الصمت
قولي يالله ..

قولي يا الله

يا الله
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:
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انه يوفقك ويعطيك العافية ..
اللهم لا حسد .. ما لقيت شي ينضااف للمقال :biggrin:

دام حضورك .. دام فرحك


آمين يارب ..

يعطيك ألف ألف عافية وشكرا لحضورك ...

روووح
02-24-2007, 02:50 AM
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مبدعه ياااملكه
الله يوفقك

ملكــة الصــمت
02-24-2007, 03:02 AM
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مبدعه ياااملكه
الله يوفقك


مشكورة حبيبي ...
مرورك دايما يسعدني ..:friends: