Encyclopedia of Molecular Biology(4334s).pdf

A-DNA

A-DNA was first recognized as a DNA structure using fiber X-ray diffraction analysis. B-DNA can

be converted to A-DNA under conditions of low hydration, and the process is reversible. The A-

DNA double helix is short and fat, with the base pairs and backbone wrapped farther away from the

helix axis (see Fig. 2 of DNA Structure ). The base pairs are significantly tilted (~19°) with respect to

the helix axis. The major groove has a very narrow width of ~3 Å and a depth of ~13 Å, whereas the

minor groove has a broad width of 11 Å and a shallow depth of 3 Å. The base pairs also display a

minor propeller twist.

There is increasing evidence that A-DNA may play an important role in biological processes such as

protein recognition and transcription regulation, as in the TATA-box sequence bound with the

TATA-box binding proteins ( 1 , 2 ). There is a sequence-dependent propensity to form A-DNA.

Guanine-rich regions readily form A-DNA, whereas stretches of adenine resist it. The crystal

structures of DNA oligonucleotides having guanine-rich sequences showed a characteristic

intrastrand guanine–guanine stacking interaction in the A-DNA double helix, which may explain the

propensity of these sequences to adopt the A-DNA conformation. Moreover, the packing of the

helices in the crystal lattice revealed a characteristic pattern of the terminal base pairs from one helix

abutting the minor groove surface of the neighboring helix, thus minimizing the accessibility of

solvent to the wide minor groove. Since a low humidity environment favors formation of A-type

helix, the displacement of surface solvent molecules by hydrophobic base pairs provides a driving

force in stabilizing short oligonucleotides in the A-DNA conformation. Recently, it has been

demonstrated that complex ions such as spermine, cobalt(III)hexamine, and neomycin can facilitate

the B-DNA to A-DNA transition for DNA containing stretches of (dG) n · (dC) n sequences.

Finally, the crystal structures of a number of DNA:RNA hybrids, such as the self-complementary r

(GCG)d(TATACGC), showed that DNA–RNA hybrid helices are of the A-DNA type. All the ribose

and 2′-deoxyribose sugars are in the C3′- endo conformation. The 2′-hydroxyl groups of the ribose

are involved in different types of hydrogen bonding to the adjacent nucleotides in the chain.

Bibliography

1. J. L. Kim, D. B. Nikolov, and S. K. Burley (1993) Nature 365 , 520–527.

2. Y. Kim, J. H. Geiger, S. Hahn, and P. B. Sigler (1993) Nature 365 , 512–520.

abl Oncogenes

The abl gene was first identified as the transforming element of Abelson murine leukemia virus (A-

MuLV), a replication-defective retrovirus that was isolated after inoculating Moloney murine

leukemia virus (M-MuLV) into prednisolone-treated BALB/c mice ( 1 ). A-MuLV induces B-cell

lymphomas in vivo and transforms both lymphoid and fibroblastic cells in vitro . The proviral

genome of A-MuLV encodes a single polypeptide chain that is a fusion product of the virally-

derived gag and cell-derived abl sequences ( 2 ). Sequence analysis of c- abl sequences revealed that,

like the src gene , the abl gene codes for a tyrosine kinase that also contains the unique, SH3, SH2,

and tyrosine kinase domains ( 3 ). Unlike the src gene, however, the abl gene product contains an

additional C-terminal domain whose function is not entirely clear. In addition, the gene product of c-

abl does not contain the negative-regulatory tyrosine residue at its C-terminus. The tyrosine kinase

activity of the c-Abl protein is negatively regulated by its SH3 domain, which is deleted from the v-

abl gene product. Interestingly, it was also found that the v- abl gene product contains a point

mutation in its C-terminal sequence, which enhances its tyrosine kinase and transforming activities

( 4 ). Thus, both the v- src and v- abl genes have alterations in their regulatory sequences that result in

the constitutive activation of their tyrosine kinase activities, which correlates with their transforming

function.

Gene mapping studies have established that the c- abl oncogene is located on human chromosome

9q34, the location where the break point occurs in the Philadelphia chromosome. The Philadelphia

chromosome is generated when a portion of the c- abl gene is translocated to chromosome 22 and is

fused to a portion of the gene called bcr , which itself is disrupted during the translocation process

(Fig. 1 ). This process results in generating a new gene, called bcr-abl , that has enhanced oncogenic

activity and whose expression leads to the development of leukemia ( 5 , 6 ). It is interesting to note

that the BCR-ABL gene is structurally similar to the gag-abl gene encoded by the Abelson murine

leukemia virus. Both the gag-abl and bcr-abl genes exhibit high levels of tyrosine kinase activity,

which is essential for their transforming activity.

Figure 1 . Generation of the bcr-abl oncoprotein by chromosomal translocation. The abl gene in a normal cell, is

located on chromosome 9 and encodes a tyrosine kinase. During malignant transformation of myeloid cells, a portion

of chromosome 9 that contains the abl locus translocates to chromosome 22 at the breakpoint cluster region (bcr) locus

and generates the chimeric bcr-abl oncoprotein. Because the translocation results in deleting the sequences that

negatively regulate abl tryosine kinase activity, the fusion protein has constitutive and increased levels of enzymatic

activity.

The function of c-abl in normal cell growth is not fully established. The c-abl gene codes for two

145-kDa proteins as a result of alternative splicing of the two first exons (see RNA Splicing and

Introns, Exons ). This results in synthesizing two proteins that differ in their amino-terminal

sequences. Both forms of c-Abl are found in the cytoplasm and in the nucleus. The c-Abl protein can

bind to DNA and to cell-cycle regulators like the retinoblastoma protein. Recent studies show that

c-abl gene expression is induced during cellular stress caused by agents, such as ionizing radiation

and certain other genotoxic agents. These agents induce the formation of a complex involving c-Abl,

DNA-dependent protein kinase, and Ku antigen ( 7 ). The DNA-dependent protein kinase in this

complex is activated by DNA damage and in turn phosphorylates and activates c-Abl. Recent

studies have also shown that c-Abl associates with the product of the ATM gene, which in turn

activates c-Abl in response to ionizing radiation. DNA damage also induces binding of c-Abl to p53

and contributes to cell-cycle arrest at the G1-phase, which is mediated by p53. Recent studies also

show that the c-Abl protein binds to protein kinase C -δ and phosphorylates the latter, resulting in its

activation and translocation to the nucleus, where it participates in inducing apoptosis ( 8 ). Thus, a

substantial amount of evidence gathered in the past few years indicates that c-Abl protein has a

pivotal role in mediating cellular growth arrest and the apoptotic effects that occur during exposure

to ionizing radiation and genotoxic stress.

Bibliography

1. H. T. Abelson and L. S. Rabson (1970) Cancer Res. 30 , 2213–2222.

2. E. P. Reddy, M. J. Smith, and A. Srinivasan (1983) Proc. Natl. Acad. Sci. USA 80 , 3623–3627.

3. C. Oppi, S. K. Shore, and E. P. Reddy (1987) Proc. Natl. Acad. Sci. USA 84 , 8200–8204.

4. S. K. Shore, S. L. Bogart, and E. P. Reddy (1990) Proc. Natl. Acad. Sci. USA 87 , 6502–6506.

5. J. Groffen, J. R. Stephenson, N. Heisterkamp, A. De Klein, C. B. Bartam, and G. Grosveld

(1984) Cell 36 , 93–99.

6. E. Shtivelman, R. P. Lifshitz, R. P. Gale, and E. Canaani (1985) Nature 315 , 550–553.

7. R. Baskaran, L. D. Wood, L. L. Whittaker, Y. Xu, C. Barlow, C. E. Canman, S. E. Morgan, D.

Baltimore, A. Wynshaw-Boris, M. B. Kastan, and J. Y. J. Wang (1997) Nature 387 , 516–519.

8. Z-M. Yuan, T. Utsugisawa, T. Ishiko, S. Nakada, Y. Huang, S. Kharbanda, R. Weichselbaum,

and D. Kufe (1998) Oncogene 16 , 1643–1648.

Abscisic Acid

1. History

The first evidence for the existence of an acidic inhibitor of coleoptile growth that promoted

abscission and seed maturation dates back to the early 1950s, but it was not until 1963 that abscisic

acid (ABA) was identified by Frederick Addicott and coworkers ( 1 , 2 ). Addicott's team was studying

compounds that stimulated abscission in cotton fruits and had named the active substances abscisin I

and abscisin II ; the latter proved to be ABA. Two other independent efforts also culminated in the

discovery of ABA. A British group headed by Wareing ( 3 ) was investigating bud dormancy of

woody plants and called the most active molecule dormin . In New Zealand, van Stevenick ( 4 )

studied compounds that accelerated abscission of flowers and fruits of Lupinus luteus . In 1964, it

became evident that the three groups had discovered the same plant hormone , which was renamed

abscisic acid 3 years later.

2. Biosynthesis and Metabolism

ABA is a universal compound in vascular plants; it is not found in bacteria, but has been reported in

green algae, certain fungi, and mosses ( 5 ). ABA is a sesquiterpenoid, with mevalonic acid as a

precursor. In certain fungi, ABA is produced by a direct, C15 pathway from farnesyl pyrophosphate.

In higher plants, ABA is derived from xanthophylls, via an indirect C40 pathway (Fig. 1 ).

Substantial progress in understanding the ABA biosynthetic pathway has been achieved by a

combination of molecular and genetic techniques, primarily on mutants in Arabidopsis thaliana, Zea

mays, Nicotiana plumbaginifolia , and tomato. Arabidopsis mutants impaired in ABA biosynthesis

were isolated on the basis of their lack of seed dormancy due to ABA deficiency and their ability to

overcome a gibberellin requirement for germination, which allowed them to germinate in the

presence of inhibitors of gibberellin biosynthesis or in a gibberellin-deficient background ( 6 , 7 ).

ABA-deficient mutants show a wilty phenotype when subjected to water stress.

Figure 1 . ABA biosynthesis in higher plants. Steps mediated by ABA1, ABA2, and ABA3 in Arabidopsis and by

VP14 in Zea mays are indicated. (Adapted from Ref. 19 .)

Mevalonic acid is converted to farnesyl pyrophosphate, a C15 compound, via several intermediates

(Fig. 1 ). The subsequent conversion of farnesyl pyrophosphate to zeaxanthin, a C40 carotenoid,

again involves multiple steps ( 8 ). A number of viviparous ( vp ) mutants of maize identify loci

corresponding to these early conversions. The transformation of zeaxanthin to all- trans -violaxanthin

consists of two epoxidations at the double bonds in both cyclohexenyl rings, with antheraxanthin as

an intermediate. The aba1 mutant impaired in zeaxanthin epoxidase activity has been characterized

biochemically in Arabidopsis ( 6 , 9 , 10 ). The N. plumbaginifolia ABA2 gene encoding zeaxanthin

epoxidase was recently cloned by transposon tagging ( 11 ). The gene encodes a chloroplast -imported

polypeptide chain with similarity to bacterial monooxygenases and oxidases. When the Nicotiana

ABA2 gene was expressed in Escherichia coli heterologously, the protein was shown to catalyze both

epoxidations in vitro . Moreover, the complementary DNA (cDNA) complemented both the N.

Plik z chomika:

Inne pliki z tego folderu:

Inne foldery tego chomika: