Info

Newly synthesized daughter strand

MLH1 endonuclease, PMS2

DNA helicase DNA exonuclease

Gap repair by DNA polymerase and ligase

▲ FIGURE 23-28 Mismatch excision repair of newly replicated DNA in human cells. A complex of the MSH2 and

MSH6 proteins binds to a mispaired segment of DNA in such a way as to distinguish between the template and newly synthesized daughter strands (step 1). This triggers binding of the MLH1 endonuclease, as well as other proteins such as PMS2, which has been implicated in oncogenesis through mismatch-repair mutations, although its specific function is unclear. A DNA helicase unwinds the helix and the daughter strand is cut; an exonuclease then removes several nucleotides, including the mismatched base (step 2). Finally, as with base excision repair, the gap is then filled in by a DNA polymerase (Pol 8, in this case) and sealed by DNA ligase (step 3).

TGFp, thereby contributing to the unregulated growth characteristic of these tumors. This finding attests to the importance of mismatch repair in correcting genetic damage that might otherwise lead to uncontrolled cell proliferation.

Nucleotide Excision Repair Was Elucidated Through Study of Xeroderma Pigmentosum, a Hereditary Predisposition to Skin Cancers

Cells use nucleotide excision repair to fix DNA regions containing chemically modified bases, often called chemical adducts, that distort the normal shape of DNA locally. A key to this type of repair is the ability of certain proteins to slide along the surface of a double-stranded DNA molecule look-

ing for bulges or other irregularities in the shape of the double helix. For example, this mechanism repairs thymine-thymine dimers, a common type of damage caused by UV light (Figure 23-29); these dimers interfere with both replication and transcription of DNA. Nucleotide excision repair also can correct DNA regions containing bases altered by covalent attachment of carcinogens such as benzo(a)pyrene and aflatoxin (see Figure 23-26), both of which cause G-to-T transversions.

Figure 23-30 illustrates how the nucleotide excision-repair system repairs damaged DNA. Some 30 proteins are involved in this repair process, the first of which were identified through a study of the defects in DNA repair in cultured cells from individuals with xeroderma pigmentosum, a hereditary disease associated with a predisposition to cancer. Individuals with this disease frequently develop the skin cancers called melanomas and squamous cell carcinomas if their skin is exposed to the UV rays in sunlight. Cells of affected patients lack a functional nucleotide excision-repair system system. Mutations in any of at least seven different genes, called XP-A through XP-G, lead to inactivation of this repair system and cause xeroderma pigmentosum; all produce the same phenotype and have the same consequences. The

Lower Your Cholesterol In Just 33 Days

Lower Your Cholesterol In Just 33 Days

Discover secrets, myths, truths, lies and strategies for dealing effectively with cholesterol, now and forever! Uncover techniques, remedies and alternative for lowering your cholesterol quickly and significantly in just ONE MONTH! Find insights into the screenings, meanings and numbers involved in lowering cholesterol and the implications, consideration it has for your lifestyle and future!

Get My Free Ebook


Post a comment